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Ligand-Exchange-Mediated Fabrication of Gold Aerogels Containing Different Au(I) Content with Peroxidase-like Behavior
Fan, X.; Cai, B.; Du, R.; Hübner, R.; Georgi, M.; Jiang, G.; Li, L.; Samadi Khoshkhoo, M.; Sun, H.; Eychmüller, A.
Noble-metal aerogels are emerging functional porous materials that have been applied in diverse fields. Among them, gold (Au) aerogels have displayed grand potentials in a wide range of catalytic processes. However, current fabrication methods fall short in obtaining Au gels with small ligament sizes and controlled surface valence states, which hinder the study of the underlying catalytic mechanisms. Here, a new approach of producing Au aerogels is reported. Via a two-phase ligand exchange, the long-chain ligands (oleylamine) of the as-prepared Au nanoparticles were replaced by short sulfide ions and subsequently self-assembled into three-dimensional gels. As a result, Au aerogels with small ligament sizes (ca. 3−4 nm) and tunable surface valence states are acquired. Taking the application for peroxidase mimics as an example, by correlating the surface valence with the catalytic properties, Au(I) is found to be the active site for H2O2 and substrate-binding site for 3,3′,5,5′-tetramethylbenzidine, paving a new avenue for on-target devising Au-based catalysts.
Chemistry of Materials 31(2019), 10094-10099
Linear stability analysis of magnetized relativistic rotating jets
Bodo, G.; Mamatsashvili, G.; Rossi, P.; Mignone, A.
We carry out a linear stability analysis of a magnetized relativistic rotating cylindrical jet flow using the approximation of zero thermal pressure. We identify several modes of instability in the jet: Kelvin-Helmholtz, current-driven and two kinds of centrifugal-buoyancy modes - toroidal and poloidal. The Kelvin-Helmholtz mode is found at low magnetization and its growth rate depends very weakly on the pitch parameter of the background magnetic field and on rotation. The current-driven mode is found at high magnetization, the values of its growth rate and the wavenumber, corresponding to the maximum growth, increase as we decrease the pitch parameter of the background magnetic field. This mode is stabilized by rotation, especially, at high magnetization. The centrifugal-buoyancy modes, arising due to rotation, tend also to be more stable when magnetization is increased. Overall, relativistic jet flows appear to be more stable with respect to their non-relativistic counterpart.
Keywords: instabilities; MHD; galaxies: jets; Astrophysics; High Energy Astrophysical Phenomena
Monthly Notices of the Royal Astronomical Society 485(2019)2, 2909-2921
- Original PDF 8,4 MB Secondary publication
Application of Flash Lamp Annealing for Controlled Nickel Silicidation of Silicon Nanowires
Silicon (Si) nanowires (NWs) have potential applications in various areas including electronics, opto-electronics and biochemical sensing. These wires are used to fabricate electronic devices with new architectures to complement the scaling down of electronic circuits. Our work focuses on one such architecture called Reconfigurable field effect transistors (RFET). An RFET is a Nickel(Ni)Si2-Si-NiSi2 Schottky junctions based device, which has an intrinsic Si channel. To fabricate an RFET, SiNWs are silicided at both ends to form Schottky junctions with the Si channel. Typically, it has two gates placed on each of the two Schottky junctions. It can be tuned to p- or n- polarity by applying appropriate electrostatic potential at one of the gates. Therefore, functional complexity and performance of electronic circuits can be enhanced using such FETs. Formation of NiSi2 is a pre-requisite for proper operation of these devices because metal work function of NiSi2 aligns itself near the mid-bandgap of Si. This enables band bending by application of an appropriate electrostatic potential for the operation of devices either as p- or as n- FET. We report our results on Ni silicidation using flash lamp annealing. By optimizing the silicidation process, control over the diffusion of Ni into the nanowire and proper silicide phase formation is achieved.
DPG-Frühjahrstagung, Regensburg, 2019, 31.03.-05.04.2019, Regensburg, Germany
Fabrication and Characterization of Reconfigurable Field Effect Transistors
To complement scaling of field effect transistors, new device concepts were introduced recently. One such concept is the reconfigurable field effect transistor (RFET). These transistors are based on nickel silicide-Si-nickel silicide Schottky junctions and their polarity can be switched between p- and n- type at runtime by the application of an electrostatic potential . Control over silicide length and phase is important for scaling and proper functioning of these devices . NiSi2 is the desirable silicide phase as its metal work function aligns itself near mid bandgap of Si, which enables reconfigurability of the device [1, 3].
We report on fabrication and electrical characterization results of RFETs. Si nanowires (SiNWs) are fabricated on undoped silicon-on-insulator (SOI) substrates by a top-down process based on electron beam lithography and inductively coupled plasma etching. Then, Ni is placed at both ends of the SiNWs by metal evaporation and lift-off processes. Afterwards, flash lamp annealing (FLA) is performed for silicidation of the NWs.
FLA has enabled better control over silicidation length since flash times are much shorter (of the order of milli-seconds) than rapid thermal annealing (RTA) times. Transmission electron microscopy (TEM) shows the formation of the desired NiSi2 phase near the silicide-Si interface. Electrical characterization of the devices with back gating shows ambipolar behaviour. For unipolar behaviour, top gates need to be fabricated, results of which will be presented at the conference.
Keywords: Schottky junction; reconfigurability; field effect transistors; nickel silicide; annealing
45th International Conference on Micro and Nano Engineering (MNE), 23.09.-26.12.2019, Rhodes, Greece
Understanding the role of carbon in active trap centre formation in porous alumina for ion beam dosimetry
Bhowmick, S.; Pal, S.; Das, D.; Singh, V.; Khan, S.; Hübner, R.; Roybarman, S.; Kanjilal, D.; Kanjilal, A.
In recent days, due to increased use of hadron therapy for cancer and tumor treatment, precise online dose monitoring is an important issue for safety purpose. Regarding hadron therapy, recently carbon ion beam with high Linear Energy Transfer (LET) is found to be more effective than the photon beams. Among several known TL/OSL oxides phosphors, C-doped alumina (Al2O3) is favorable for radiation dosimetry, especially in medical field due to its tissue equivalent in terms of radiation absorption, simple glow curve, and high sensitivity. A facile approach to improve thermoluminescence sensitivity of electrochemically anodized porous Al2O3 (AAO) is presented by introducing carbon ions for ion beam dosimetry. Initially, ion implantation technique has been carried out for Carbon doping in AAO in controlled manner. HAADF-STEM, EDS mapping, SEM studies reveal the evolution of a porous structure followed by the carbon distribution up to 200 nm. However, the evolution of optically active F+ centres with increasing ion fluence has been examined by photoluminescence investigation at room temperature and thermoluminescence (TL) measurement while the chemical nature of such defect centres has been extracted by depth dependent XPS analysis.
APS March Meeting 2019, 04.-08.03.2019, Boston, MA, USA
Development of highly affine fluorinated ligands and 18F-labelled radiotracers for PET imaging of the adenosine A2A receptor
Adenosine is an essential neuromodulatory molecule that acts via four G-protein coupled receptors (A1R, A2AR, A2BR, A3R). In the central nervous system (CNS), the A2AR is highly concentrated in the striatum. The A2AR is a promising target for positron emission tomography (PET) imaging of neurodegenerative diseases, such as Huntington’s disease (HD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Istradefylline is the first A2AR antagonist that is approved by the U.S. Food and Drug Administration (FDA) for adjunctive treatment in patients with PD. So far, [18F]MNI-444 [Ki (hA2AR) = 2.8 nM] is the only 18F-labelled A2AR radiotracer evaluated in healthy subjects.
Aiming at the development of A2AR radiotracers with improved molecular imaging properties, this study is based on three recently published lead compounds with a pyrazolo[3,4-d]pyridine, a morpholinobenzo[d]thiazol-2-amine and a pyrazolo[4,3‑e]‑1,2,4-triazolo[1,5‑ c]-pyrimidine scaffold. Herein, a series of 30 fluorinated derivatives was developed by systematic modification of selected lead compounds. The binding affinities torwards the A2AR and the adenosine A1 receptor (A1R) subtypes were determined by in vitro radioligand binding assays. Regarding the binding affinity and selectivity, PYP1 [Ki (hA2AR) = 5.29 nM, Ki (hA1R) = 220 nM)], PYP2 [Ki (hA2AR) = 2.13 nM, Ki (hA1R) = 147 nM)] und TOZ1 [Ki (hA2AR) = 1.00 nM, Ki (hA1R) = 618 nM)] were radiolabelled as the most suitable A2AR ligands in order to perform first preclinical studies in mice. Additionally, FLUDA [Ki (hA2AR) = 0.61 nM, Ki (hA1R) = 767 nM] was developed and radiolabelled based on the known PET radiotracer [18F]FESCH. [18F]FESCH was selected as reference compound and thus, its radio-synthesis was established as well as optimised in our laboratories.
Three different labelling strategies have been investigated in the frame of this work: (i) two-step one-pot radiolabelling procedures using 18F-labelled prosthetic groups, (ii) alcohol-enhanced copper-mediated one-step radiolabelling procedures starting from boronic acid pinacol ester precursors and (iii) conventional one-step radiolabelling procedures starting from nitro precursors. After the successful radiosynthesis, all five A2AR radiotracers were evaluated by in vitro and in vivo experiments. In vitro autoradiography on mice brain slices revealed specific binding of [18F]PPY2, [18F]TOZ1 and [18F]FLUDA in the region of interest (striatum). Metabolism studies in mice showed a fast metabolic degradation of [18F]PPY1 and [18F]PPY2 with the formation of brain penetrating radiometabolites. In contrast, [18F]TOZ1 and [18F]FLUDA displayed a higher metabolic stability in vivo as the reference [18F]FESCH. PET studies of [18F]PPY1, [18F]PPY1 and [18F]TOZ1 in CD-1 mice revealed no specific accumulation in striatum which would be non-consistent with the known A2AR distribution pattern. The findings indicate that these radiotracers may not demonstrate sufficient affinity in vivo for PET imaging of the A2AR in the brain. In contrast to the previous results, striatum was clearly visualized in PET studies with [18F]FLUDA. Altogether [18F]FLUDA revealed improved molecular imaging properties compared [18F]FESCH which might be a result of the introduction of deuterium atoms in the [18F]fluoroethyl chain, thus resulting in an increased metabolic stability.
In conclusion, the preclinical evaluation of the new developed radiotracers demonstrated that [18F]FLUDA has the highest potential to provide information about the A2AR expression by PET imaging of the brain. Hence, we focus on the clinical translation of [18F]FLUDA to study the A2AR expression in patients with Parkinson’s disease.
Keywords: adenosine A2A receptor; radiofluorination; PET imaging; Parkinson’s disease
Universität Leipzig, 2020
Mentor: Prof. Peter Brust
Development and biological evaluation of [18F]FLUDA for clinical translation to image the adenosine A2A receptor with PET
The adenosine A2A receptor (A2AR) is related to the pathogenesis of several brain diseases and is assumed to mediate immunsuppressive processes related to cancer pathology. Thus, A2AR radiotracers for PET imaging are promising candidates for the differential diagnosis of neurodegenerative diseases, in particular Parkinson’s disease, and to study the A2AR within the tumor environment. We developed [18F]FLUDA based on the deuteration of the [18F]fluoroethoxy chain of [18F]FESCH [1,2] to improve imaging properties in mice. [18F]FLUDA was evaluated pre-clinically prior to a first-in-human trial.
Binding affinities of FLUDA towards the human A2AR and A1R subtypes were estimated in vitro by competitive radioligand binding assays. [18F]FLUDA was synthesized by a two-step one-pot approach. In vitro autoradiography of [18F]FLUDA was performed on mice brain cryosections. In vivo evaluation of [18F]FLUDA was carried out in a CD-1 mouse by radio-HPLC analysis of plasma and brain samples (15 min p.i.) and dynamic PET/MR studies under baseline (n = 4) and blocking conditions (2.5 mg tozadenant per kg, 15 min before tracer, n = 4). The cerebellum was used as a reference tissue. The time-activity curves were obtained and the SUV ratio (SUVR) of striatum over cerebellum were used as measure for specific uptake.
In vitro binding studies revealed no influence of deuteration on the estimated binding affinities with Ki values of FLUDA and FESCH towards human A2AR of 0.60 nM and 0.61 nM, respectively. The radiosynthesis of [18F]FLUDA was successfully established (Fig.1). A single experiment indicates that [18F]FLUDA is metabolically more stable in mouse than [18F]FESCH. While no radiometabolites were found for [18F]FLUDA in plasma and brain samples at 15 min p.i., for [18F]FESCH the percentages of intact radiotracer were 71% and 41% in brain and plasma samples, respectively. By in vitro autoradiography [18F]FLUDA demonstrated a specific accumulation in the striatum, which is characterized by the binding parameters KD = 4.3 ± 0.7 nM and Bmax = 556 ± 143 fmol/mg wet weight (Fig.2A). PET scans revealed a selective binding of [18F]FLUDA in striatum (SUVR15 30 min p.i. >8), which was significantly reduced by tozadenant pre-treatment by 30% (p<0.05, Fig.2B/C).
The two-step one-pot radiosynthesis of [18F]FLUDA was successfully implemented for preclinical studies. Due to the promising preclinical results in mice, we focus on the clinical translation of [18F]FLUDA. Based on the performed single dose toxicity study of FLUDA we don’t expect any adverse effects. Currently, we are working on the radiation dosimetry of [18F]FLUDA in piglets and its implementation for clinical application.
The authors thank the European Regional Development Fund and Sächsische Aufbaubank (SAB) for financial support (project no. 100226753).
(1) Bhattacharjee et al., Nucl Med Biol 2011, 38, 897-906; (2) Khanapur et al., J Med Chem 2014, 57, 6765-80
Keywords: Adenosine A2A Receptor; [18F]FLUDA; Fluorine-18; PET; Brain
15th European Molecular Imaging Meeting, 24.-28.08.2020, online, online
Ion beams for information technology
Taking the advancing of accelerator technologies, a variety of ions (all stable elements and some radioactive elements) in a wide energy range from eV to GeV can be produced and injected into targets. Using the chemical effect of injected ions, “ion implantation" has been well established to dope semiconductors and integrated into the standard microelectronics production line in Si-chip technology. Ion irradiation refers to using other effects rather than the doping effect in materials and has been used for defect (or lifetime) engineering in microelectronics. Moreover, ion beams are also instrument for the analysis of solid state surfaces to get the information about the composition and impurity lattice location. In this talk, I will give some examples for the application of ion beams in information technologies. The following topics will be included: (1) Doping semiconductors well above the solid solidity limits: by doing so the semiconductors can be ferromagnetic or superconducting [1-5]. (2) Defect engineering in SiC: defects can carry magnetic moments giving possibilities for ferromagnetic coupling in SiC as well as for manipulating single defect center for quantum technology [6, 7]. (3) Defect engineering in oxides: it can introduce uniaxial strain and change the properties rather than by choosing different growth substrates [8, 9]. It is worthy to note that ion beam technology has been well developed for applications at wafer (450 mm) scale. Once the proof-of-concept is done, these applications mentioned above can be easily transferred to industries.
 M. Khalid, et al., Phys. Rev. B 89, 121301(R) (2014).
 S. Zhou, J. Phys. D: Appl. Phys. 48, 263001(2015).
 Y. Yuan, et al., Phys. Rev. Materials 1, 054401 (2017).
 M. Wang, et al., Phys. Rev. Applied. 11, 054039 (2019).
 S. Prucnal, et al., Phys. Rev. Materials 3, 054802 (2019).
 S. Zhou, X. Chen, J. Phys. D: Appl. Phys. 52, 393001 (2019).
 C. Kasper, et al., arXiv:1908.06829v1 (2019).
 P. Pandey, et al., APL Materials 6, 066109 (2018).
 C. Wang, et al., Topological Hall effect in single thick SrRuO3 layers induced by defect engineering, submitted (2019).
Invited seminar at Institute of Semiconductors, CAS, 14.11.2019, Beijing, China
Invited seminar at Tsinghua University, 15.11.2019, Beijing, China
Extended room-temperature infrared photoresponse in hyperdoped Si by ion implantation
Presently, silicon photonics requires photodetectors that are sensitive in a broad infrared range, can operate at room temperature, and are suitable for integration with the existing Si technology process. Here, we demonstrate strong room-temperature sub-bandgap photoresponse of photodiodes based on Si hyperdoped with chacolgen ions. The epitaxially recrystallized hyperdoped Si layers are developed by ion implantation combined with pulsed laser melting and incorporate Se/Te dopant concentrations several orders of magnitude above the solid solubility limit. With increasing the impurity concentration, the hyperdoped Si is changed from insulating to quasi-metallic with a finite conductivity as the temperature tends to zero. The optical absorptance is found to increase monotonically with increasing dopant concentration and extends well into the mid-infrared range. Temperature-dependent optoelectronic photoresponse unambiguously demonstrates that the extended infrared photoresponsivity from hyperdoped Si p-n photodiodes is mediated by an impurity band within the upper half of the Si bandgap. This work contributes to pave the way towards establishing a Si-based broadband infrared photonic system operating at room temperature.
References: Sci. Reports 7, 43688 (2017), Phys. Rev. Appl. 10, 024054 (2018) and Adv. Mater. Inter. 5, 1800101 (2018), Phys. Rev. Applied 11, 054039 (2019).
Invited lecture (Conferences)
14th National Conference on Laser Technology and Optoelectronics, 17.-20.03.2019, Shanghai, China
Invited lecture (Conferences)
2nd International Conference on Radiation and Emission in Materials, 15.-18.12.2019, Bangkok, Thailand
Ion irradiation effect in complex oxides: Another degree of freedom or complexity?
Inter-relations among charge, spin, orbital and lattice parameters are largely demonstrated in multi-functional oxide materials, which exhibit a variety of exotic properties, ranging from superconductivity, insulator-metal transition, colossal magnetoresistance, charge ordering, and orbital ordering, etc. In particular, tilting a delicate energy balance in lattice interactions and kinetics, achieved by temperature, pressure or chemical control, may result in exotic phenomena in these systems. However, fine-tailoring such interactions has proven difficult. In this context, defect engineering by ion irradiation, which can introduce strain and electronic disorder, has emerged as a powerful technique to fine tune complex phases of oxide thin films. In this contribution, we show that ion irradiation can modify the magnetic and electrical transport properties in a broad variety of materials, including spinel NiCo2O4, perovskite BiFeO3, SrRuO3 and LaNiO3 [1-4]. Diverse magnetic, structure and magneto-transport modifications, which are inaccessible by conventional film growth methods, have been obtained. For instance, the transport in LaNiO3 can be driven from metallic phase into an Anderson insulator by directly tuning the electronic mean free path via irradiation-induced disorder . In BiFeO3, we have obtained a super-tetragonal phase with the largest c/a ratio ~ 1.3 that has ever been experimentally achieved in BiFeO3 . This may lead to strong polarization enhancement. By comparing the effect in different materials, we will also point out the complexity in understanding the tailoring of oxides by ion beams.
 P. Pandey, Y. Bitla, M. Zschornak, M. Wang, C. Xu, J. Grenzer, D. C. Meyer, Y. Y. Chin, H. J. Lin, C. T. Chen, S. Gemming, M. Helm, Y. H. Chu, S. Zhou, Enhancing the Magnetic Moment of Ferrimagnetic NiCo2O4 via Ion Irradiation driven Oxygen Vacancies, APL Materials 6, 066109 (2018)
 C. Chen, C. Wang, X. Cai, C. Xu, C. Li, J. Zhou, Z. Luo, Z. Fan, M. Qin, M. Zeng, X. Lu, X. Gao, U. Kentsch, P. Yang, G. Zhou, N. Wang, Y. Zhu, S. Zhou, D. Chen, J. Liu, Controllable defect driven symmetry change and domain structure evolution in BiFeO3 with enhanced tetragonality, Nanoscale 11, 8110 (2019)
 C. Wang, C. Chen, C.-H. Chang, H.-S. Tsai, P. Pandey, C. Xu, R. Böttger, D. Chen, Y.-J. Zeng, X. Gao, M. Helm, S. Zhou, Defect-induced exchange bias in a single SrRuO3 layer, ACS Appl. Mater. Interfaces, 27472 (2018).
 C. Wang, C.-H. Chang, A. Huang, P.-C. Wang, P.-C. Wu, L. Yang, C. Xu, P. Pandey, M. Zeng, R. Böttger, H.-T. Jeng, Y.-J. Zeng, M. Helm, Y.-H. Chu, R. Ganesh, S. Zhou, Tunable disorder and localization in the rare-earth nickelates, Phys. Rev. Materials 3, 053801 (2019)
64th Annual Conference on Magnetism and Magnetic Materials, 03.-08.11.2019, Las Vegas, US
Seminar talk at DESY, 06.-07.05.2019, Hamburg, Deutschland
Ferromagnetism and Anisotropic Spinodal Phase Separation in (In,Fe)As
We report on the experimental observation and theoretical studies of a self-assembled Fe-rich (In,Fe)As nano-lamellar structure that is driven by anisotropic spinodal decomposition at the growth front during laser heating-induced recrystallization of Fe-implanted InAs . Pseudomorphically embedded in the InAs lattice, those Fe-rich nano-lamellae are perpendicular to the (001) surface and parallel to the in-plane  crystallographic direction. The Fe atoms are substitutionally incorporated at the indium sites. Magnetic measurements indicate a typical blocked superparamagnetic behavior suggesting strong ferromagnetic orderings inside the Fe-rich nanostructures, but weak coupling between the nano-lamellae. Our findings explain the surprisingly high apparent Curie temperatures and unexpected eight-fold symmetry of crystalline anisotropic magnetoresistance found previously in Be-doped n-type (In,Fe)As grown by molecular beam epitaxy . Prompted by these results we discuss how a different d-level electronic configuration of Fe in InAs and Mn in GaAs  affects the magnetic ion incorporation and spatial distribution and, thus, magnetism and anisotropy. Our results also indicate that the directional distribution of impurities or alloy components setting in during the growth may account for the observed nematicity in other classes of correlated systems.
 Y. Yuan, R. Hübner, M. Birowska, C. Xu, M. Wang, S. Prucnal, R. Jakiela, K. Potzger, R. Böttger, S. Facsko, J.A. Majewski, M. Helm, M. Sawicki, S. Zhou, T. Dietl, Nematicity of correlated systems driven by anisotropic chemical phase separation, in Phys. Rev. Materials 2, 114601 (2018).
 Pham Nam Hai, D. Sasaki, Le Duc Anh, and M. Tanaka, Crystalline anisotropic magnetoresistance with twofold and eight-fold symmetry in (In,Fe)As ferromagnetic semiconductor, Appl. Phys. Lett. 100, 262409 (2012).
 M. Birowska, C. Śliwa, J. A. Majewski, and T. Dietl, Origin of Bulk Uniaxial Anisotropy in Zinc-Blende Dilute Magnetic Semiconductors, Phys. Rev. Lett. 108, 237203 (2012).
64th Annual Conference on Magnetism and Magnetic Materials, 03.-08.11.2019, Las Vegas, US
Near-Surface Cobalt Implantation Into Amorphous Carbon Films: Observation Of Complex Magnetic Nanostructures And Multiple Magnetic Phases
Suschke, K.; Gupta, P. G. S.; Williams, G. V. M.; Hübner, R.; Kennedy, J.; Markwitz, A.
Magnetic nanoclusters in amorphous carbon have promising applications for highly responsive magnetic sensors, where decreasing the size of the nanoclusters can lead to superparamagnetism and therefore low remanence. The insulating properties (wide bandgap) of amorphous carbon are also potentially useful for designing high frequency components. Both these properties are crucial to achieve ultra-high density magnetic data storage.
High fluence (1.2×1017 Co/cm2) near-surface implantation of 30 keV Co ions into amorphous carbon results in the formation of complex magnetic nanostructures and multiple magnetic phases. Next to small segregated cobalt carbide nanoclusters, starting forming at a depth of 25 nm within the amorphous carbon film, a nearly continuous network of cobalt carbide thin nanocrystalline regions can be observed at a depth of 8 nm. On the surface a 3 nm thin cobalt oxide nanostructured layer is seen separated from the cobalt carbide by a 1 nm thin Co-depleted region. TEM and magnetic measurements show superparamagnetic nanoclusters with a blocking temperature of 5 K. However, a small proportion of larger cobalt carbide nanoclusters exhibits magnetic hysteresis even at room-temperature. The magnetic saturation moment is as high as 0.51 µB/Co at 2 K and 0.32 µB/Co at room temperature - ten times larger than previously reported on hydrogenated amorphous carbon . The structural disorder of the nanoparticles results in a spin glass behaviour with a range of transition temperatures below ~70 K, suggesting a spin disordered shell model . Thus high fluence Co-implantation into amorphous carbon at room temperature created complex magnetic nanostructures consisting of cobalt oxide and cobalt carbide. Multiple magnetic phases such as superparamagnetism, spin glass, ferromagnetism and also antiferromagnetism can be observed.
1. P.G. Sridhar Gupta, G.V.M. Williams and A. Markwitz, Journal of Physics D: Applied Physics, 2016, 49, 5, 055002.
2. T. Prakash, G.V.M. Williams, J. Kennedy and S. Rubanov, Materials Research Express, 2016, 3, 12, 126102.
9th International Conference on Advanced Materials and Nanotechnology, AMN9, 10.-14.02.2019, Wellington, New Zealand
Simultaneous optical measurement of temperature and velocity fields in solidifying liquids
We introduce a complex image processing scheme for the simultaneous application of liquid crystal thermometry (LCT), in addition to the previously established method in Anders et al. (Exp Fluids 60(4):68, 2019. https ://doi.org/10.1007/s00348-019-2703-8) for particle tracking velocimetry and particle image velocimetry. This scheme was developed for an experimental study on the double-diffusive convection in an aqueous ammonium chloride solution NH4Cl(aq) during crystallization. The use of thermochromic liquid crystals (TLC) enables to visualize the flow and temperature field simultaneously. We present a color interpolation method that enhances the accuracy of the LCT by yielding RGB images only representative of the TLC’s coloration. An artificial neural network (ANN) which processes RGB triplets and spatial color dependencies transforms these images into temperature fields. The combination of the ANN system and a corresponding calibration procedure enhances the accuracy and measurable temperature range of the LCT compared to state-of-the-art procedures. By using the here established measurement scheme, quantitative global studies of the mutual influence between solidification and convection are enabled and exemplary results are presented.
Keywords: multiphase flow; double-diffusive convection; solidification; liquid crystal thermometry; artificial neural network; TLC; PIV; PTV; PITV
- Spectral random masking: a novel dynamic masking technique … (Id 28683) is referenced by this (Id 30227) publication
Experiments in Fluids 61(2020), 113
Online First (2020) DOI: 10.1007/s00348-020-2939-3
Selektive Trennung von Rhenium und Molybdän mittels Solventextraktion – Untersuchung von supramolekularen Wechselwirkungen und Komplexbildung
Nestel, J.; Helbig, T.; Kelly, N.
Rhenium ist ein sehr seltenes Element. Die Häufigkeit in der Lithosphäre liegt in der Größenordnung von Gold. Als Hochtechnologiemetall erfährt Rhenium insbesondere zur Fertigung hochwarmfester Superlegierungen steigende Nachfrage. Sowohl in den natürlichen Lagerstätten, als auch in Sekundärrohstoffen, liegt Rhenium häufig gemeinsam mit Molybdän vor.
Im Rahmen der Solventextraktion von Re(VII) und Mo(VI) aus saurer Lösung mittels aliphatischer Amine wurde bereits in den 1980er Jahren ein Effekt beschrieben, der bei Zusatz von Organophosphorderivaten eine selektive Trennung von Re(VII) und Mo(VI) bei der Reextraktion ermöglicht. Die vorliegende Arbeit nutzt FTIR-Spektroskopie und mehrdimensionale NMR-Experimente, um die Ursachen für die selektive Trennung der beiden Elemente zu belegen und Wege zu ihrer Optimierung aufzuzeigen.
Die Ergebnisse der selektiven Reextraktion (Stripping) werden in Übereinstimmung mit den spektroskopischen Befunden vor dem Hintergrund ihrer supramolekularen Ursachen präsentiert.
DECHEMA Jahrestagung der Fachgruppen Extraktion und Phytoextraktion, 07.-08.02.2019, Muttenz, Schweiz
Probing the role of bound excitons in optical properties of titanium dioxide anatase from first principles
The electronic structure and optical spectra of anatase titanium dioxide is computed by combining state-of-the-art density functional theory (DFT) and many-body perturbation theory (MBPT). Excitonic optical spectra is computed by solving Bethe-SalpeterEquation (BSE). From the solution of BSE and also from the analysis of charge distribution the photo-generated excitons in anatase is shown to be strongly bound and localized. Such typical behavior of intrinsic excitons in bulk anatase makes it a material which shows superior performance in photo catalysis, photovoltaics, optoelectronics and in nonlinear optical regime.
Keywords: Excitons; optical properties; titanium dioxide; first-principle calculations
64th DAE Solid State Physics Symposium, 18.-22.12.2019, Jodhpur, Rajasthan, India
Correlative microscopy of relevant ex-vivo and in-vitro biological systems by multimodal optical and high resolution ion/electron based techniques
Podlipec, R.; Klingner, N.; Heller, R.; Kriselj, A.; Pelicon, P.; Strancar, J.; von Borany, J.
Correlative microscopy combining light and electron microscopy (CLEM) has become one of the important and unmissable tools in various investigations of complex biological systems revealing high-resolution structural and highly-specific functional information . In the last years more combinations of other advanced techniques have been developed, such as combining optical microscopy with atomic force spectroscopy/microscopy (AFM) or with magnetic resonance imaging, etc  whereas in our study multimodal optical microscopy has been correlated with ion and electron based techniques such as is helium ion microscopy (HIM) . The purpose for using combination of the complementary techniques was to elucidate or better interpret specific biological problems which could not be explained just by one technique lacking of whether resolution, sensitivity of specificity. We focused on toxicology related scientific questions of how inhaled nanoparticles interact with lung epithelial cells/tissue once get into direct contact and why interactions can eventually lead to diseases and potentially persistent inflammation [4,5]. In order to better understand the interaction on nanometer scales we first developed proper lung in-vitro model which was followed by proper sample preparation for efficient correlative microscopy using multimodal optical microscopy and high resolution HIM microscopy. By latter we managed to image single metal oxide nanoparticles on cell surfaces interacting with cell membranes, while functional information of the same events was prior measured with confocal and super-resolution optical microscopy. Besides, we implemented described correlative microscopies also for scientific problem related to rejection of hip implants where material debris is found everywhere in the surrounding periprosthetic tissue with lack of knowledge what happens on a molecular scale. The latest findings of both ongoing studies will be presented.
1. P. de Boer, JP Hoogenboom, BNG Giepmans, Nature Methods 12, 503-513 (2015).
2. T Ando, et. Al, Journal of Physics D: Applied physics 44, (2018)
3. G Hlawacek. et Al. Helium Ion Microscopy. J. Vac. Sci. Technol. 32, (2014)
4. Li, X., Jin, L. & Kan, H. Air pollution: a global problem needs local fixes. Nature 570, 437–439 (2019).
5. E Underwood. The polluted brain. Science 355, 342–345 (2017).
Keywords: CLEM; Helium Ion Microscopy; FLIM microscopy; lung epithelium; TiO2 nanotubes; hip implants; periprosthetic tissue; metal debris
Invited lecture (Conferences)
Seminar of Croatian Biophysical Society, 16.12.2019, Zagreb, Croatia
Upscaling High-Resolution Mineralogical Analyses to Estimate Mineral Abundances in Drill Core Hyperspectral Data
In this paper, we propose a supervised learning method for estimating mineral quantities in drill core hyperspectral data. Our proposed method links the high-resolution mineralogical analyses and hyperspectral data to learn a dictionary. The learned dictionary is then used for linear unmixing and estimating mineral abundances of the entire drill core sample. To evaluate the performance of the proposed method, we use a drill core data set, which is composed of the VNIR-SWIR hyperspectral data and high-resolution mineralogical analyses performed by a Scanning Electron Microscopy (SEM) instrument equipped with the Mineral Liberation Analysis (MLA) software. The quantitative and qualitative analysis of the experimental results shows that the proposed method provides reliable mineral quantity estimates.
Keywords: Hyperspectral drill core data; highresolution mineralogical analysis; upscaling; dictionary learning
Contribution to proceedings
IGARSS 2019-2019 IEEE International Geoscience and Remote Sensing Symposium, 28.07.-02.08.2019, Yokohama, Japan
Zustandsüberwachung von Transport- und Lagerbehältern für abgebrannte Brennelemente und wärmeentwickelnde HAW bei verlängerter Zwischenlagerung – strahlungsbasierte, thermographische und akustische Messverfahren
Wagner, M.; Fiß, D.; Schmidt, S.; Reinicke, S.; Kratzsch, A.; Hampel, U.
Bis ein Endlager in tiefen geologischen Formationen zur Verfügung steht, besteht in Deutschland Bedarf für die sichere Zwischenlagerung abgebrannter Brennelemente an den Kraftwerksstandorten. Es wird davon ausgegangen, dass erhebliche Zeiträume von mehr als 50 Jahren zu berücksichtigen sind. Dadurch ergeben sich verschiedene regulatorische und sicherheitstechnische Fragestellungen. Eine davon ist die nach der Langzeitintegrität der Brennelemente in den Behältern. Ihre Beantwortung hat direkte Relevanz für den späteren Transport zum Endlager und die Umladung des abgebrannten Kernbrennstoffs in andere Behälter. Im Rahmen des vom BMWi geförderten Vorhabens DCS-MONITOR untersuchen wir Potenziale und Grenzen von nichtinvasiven Verfahren zur Überwachung des Zustands des radioaktiven Inventars von Trockenlagerbehältern. Als solche betrachten wir die Thermographie, strahlungsbasierte Messverfahren sowie akustische Messverfahren.
Invited lecture (Conferences)
Fachworkshop Zwischenlagerung, 22.-23.10.2019, Berlin, Deutschland
An analysis for detecting potential relocation of the inventory of dry storage containers during prolonged interim storage via changes in the wall temperature fields
Wagner, M.; Reinicke, S.; Kratzsch, A.; Hampel, U.
We investigated the suitability of thermography for detecting a potential relocation of the inventory of dry storage containers of type CASTOR V/19. We used numerical simulations of the heat transfer in the container to determine the sensitivity of the wall temperature distribution to such changes. We conducted an analysis for three different hypothetical damage cases: a 9 cm compaction of the fuel in all fuel rods of a single fuel assembly, the same compaction in all fuel assemblies and a compaction of all fuel assemblies by 50 %. The analysis shows that the temperature difference between intact case and all three damage cases after 40 years is too low for an accurate detection becoming even lower for longer storage periods. Temporal thermal insulation of the containers may increase the temperature gradients but reducing the spatial resolution.
Keywords: interim storage; heat transfer
- Data for: An analysis for detecting potential relocation … (Id 31409) HZDR-primary research data are used by this (Id 30221) publication
Nuclear Engineering and Design 366(2020), 110749
Ternary MIn2S4 (M = Mn, Fe, Co, Ni) thiospinels - crystal structure and thermoelectric properties
Wyżga, P.; Veremchuk, I.; Bobnar, M.; Hennig, C.; Leithe-Jasper, A.; Gumeniuk, R.
The combined structural, magnetic and thermoelectric study of polycrystalline ternary MIn2S4 (M = Mn, Fe, Co, Ni) thiospinels is presented. All compounds crystallize with MgAl2O4-type structure. Rietveld refinement analysis confirmed that the preferred crystallographic position of transition metal element changes from mainly tetrahedral 8a for Mn to exclusively octahedral 16d for Ni (i.e. increase of the inversion parameter). The magnetic susceptibility measurements revealed M-elements to possess 2+ oxidation state in MIn2S4. All these compounds order antiferromagnetic with Néel temperature TN ranging from 5–13 K. Studied thiospinels are n-type semiconductors with large values of electrical resistivity ρ > 0.6 Ω∙m at RT. An increase of inversion parameter leads to reduction of determined activation energies, as well as to the more disorder-like behavior of thermal conductivity. The highest thermoelectric figure of merit ZT was observed for MIn2S4 with M = Fe, Ni, which adopt inverse spinel structure.
Keywords: thiospinel; powder diffraction; magnetic susceptibility; thermoelectric properties
Zeitschrift für Anorganische und Allgemeine Chemie 646(2020)14, 1091-1098
Ultra-trace Detection of 99Tc in Environmental Samples by Accelerator Mass Spectrometry
In our project we are developing methods for the detection of the anthropogenic radionuclide 99-Technetium by Accelerator Mass Spectrometry (AMS). For environmental samples, a highly effective chemical sample preparation method was developed, that removes a large fraction of the interfering elements Ruthenium and Molybdenum and embeds the Tc in a Niobium matrix. The samples were measured at the AMS setup of the Maier-Leibnitz-Laboratory in Munich by extraction of 99TcO− from the ion source, stripping to 99Tc12+ and normalizing to the 93Nb11+ current. A particle energy of 150 MeV in combination with the detection via a Time-of-Flight path and the Gas-filled Analyzing Magnet System (GAMS) allows for a sensitivity of 5·1E6 atoms per sample. The method is discussed together with results from environmental samples. In particular, 99Tc concentrations along a water column from the Pacific Ocean, as well as in porewater from an Austrian peat-bog are presented.
Keywords: AMS 99Tc
Contribution to WWW
eingereichtes Abstract für abgesagte DPG-Frühjahrstagung: https://www.dpg-verhandlungen.de/year/2020/conference/hannover/part/ms/session/8/contribution/5
AMS of 90Sr at the sub-fg-level using laser photodetachment at VERA
The fission product 90Sr (T1/2 = 28.9 a) is of interest in environmental sciences for its radiotoxicity as well as a potential tracer. Limits of detection (LoD) of mass spectrometric methods such as ICP-MS, RIMS or conventional AMS are close to the radiometric limit of 3 mBq.
The main problem in AMS of 90Sr is the strong interference of the stable isobar 90Zr. This problem can be overcome with the new Ion Laser InterAction Mass Spectrometry (ILIAMS) setup at the Vienna Environmental Research Accelerator (VERA). It provides near complete suppression of elemental or molecular isobars via selective laser photodetachment inside a gas-filled radiofrequency quadrupole (RFQ). With 10W of laser power from a 532nm cw-laser and a He+O2 mixture as buffer gas, ILIAMS achieves a suppression factor for 90Zr of 10⁷. Extracting SrF₃^− out of the ion source and elemental separation inside an ionization chamber gives an additional Zr suppression of 10⁵.
Measurements with dilution series of reference materials were successfully conducted. The overall Sr detection efficiency is 0.4 %₀ and the
blank level 90Sr/Sr=(4.5 ± 3.2)×10^−15. This corresponds to a more than tenfold improved LoD of 0.1 mBq.
Contribution to WWW
eingereichtes Abstract für abgesagte DPG-Frühjahrstagung: https://www.dpg-verhandlungen.de/year/2020/conference/hannover/part/ms/session/10/contribution/8
Application of AMS to the research on nuclear waste disposal safety
At the Grimsel Test Site (Switzerland), several in situ tracer tests aim at studying the possible radionuclide release from the bentonite engineered barrier system and the processes which may lead to their subsequent migration though the granodiorite host rock. We investigate the diffusion of Tc-99 and actinides (AN) through bentonite and the remobilization over a time period of several years of the AN tracers employed in previous in situ tests. AMS is the ultra-trace analysis method of choice for studying the behaviour of Tc-99 and AN with concentration at and below fg/g levels in such dedicated long-term in situ tests, providing results that contribute to the safety evaluation of future nuclear waste repositories.
Keywords: AMS Tc-99
Contribution to WWW
eingereichtes Abstract für abgesagte DPG-Frühjahrstagung: https://www.dpg-verhandlungen.de/year/2020/conference/hannover/part/ms/session/8/contribution/4
Modeling of the free-surface vortex driven bubble entrainment into water
The recently developed GENTOP (Generalized Two Phase Flow) concept which bases on the multi-field Euler-Euler approach was applied to model a free-surface vortex - a flow situation which is relevant for hydraulic intake. A new bubble entrainment model has been developed and implemented in the concept. In general a satisfying agreement with the experimental data can be achieved. However, the gas entrainment can be largely affected by several parameters or models used in the CFD (Computational Fluid Dynamics) simulation. The scale of curvature correction C_scale in the turbulence model, the coefficient in the entrainment model C_ent and the assigned bubble size to be entrained has significant influence on the gas entrainment rate. The gas entrainment increases with higher C_scale which can be attributed to the stronger rotation captured by the simulation. A smaller bubble size gives higher gas entrainment while a larger bubble size leads to a smaller entrainment with a periodical peak of entrainment in its transient profile. The results also show that the gas entrainment can be controlled by adjusting the entrainment coefficient C_ent. Basing on the modeling framework presented in this paper further improvement on the physical modeling of the entrainment process should be done.
Keywords: Multiphase flow; Bubble entrainment; Free-surface vortex; Rotating flow; GENTOP
Water 12(2020)3, 709
Ion Laser Interaction Mass Spectrometry - status and prospects
The Ion Laser InterAction Mass Spectrometry (ILIAMS) technique at the Vienna Environmental Research Accelerator (VERA) tackles the problem of elemental selectivity in AMS. It achieves near-complete suppression of isobar contaminants via selective laser photodetachment of decelerated anion beams in a gas-filled radio frequency quadrupole cooler. The technique exploits differences in electron affinities (EA) within elemental or molecular isobaric systems neutralizing anions with EAs smaller than the photon energy. Collisional detachment or chemical reactions with the buffer gas can further enhance anion separation.
In AMS of 36Cl and 26Al, ILIAMS reliably provides isobar suppression of more than 10 orders of magnitude. Furthermore it already enables measurements of 90Sr, 135,137Cs and 182Hf with unprecedented sensitivity at VERA and allows to study anion chemistry at eV energies.
Current research focusses on extending this technique to 41Ca, 53Mn, 59Ni, 99Tc and 107Pd. Exotic species such as double-negatively charged carbon clusters complete the cooler ’guestbook’. This contribution will give an overview over these achievements and prospects of the ILIAMS-technique for the near future.
Contribution to WWW
eingereichtes Abstract für abgesagte DPG-Frühjahrstagung: https://www.dpg-verhandlungen.de/year/2020/conference/hannover/part/ms/session/10/contribution/6
Supernova-produced 53Mn on Earth
For the age range from 1.5 to 4 Myr ago we found in deep ocean ferromanganese crusts an excess concentration in terms of 53Mn/Mn of about 4 · 10−14 over that expected for cosmogenic production. We conclude that this 53Mn is of supernova origin because it is detected in the same time window, about 2.5 Myr ago, where 60Fe has been found earlier. This overabundance confirms unambiguously the supernova (SN) origin of that 60Fe. For the first time supernova-formed 53Mn has been detected and it is the second positively verified radioisotope from the same supernovae. The ratio 53Mn/60Fe of about 12 is consistent with that expected for a SN with a 11 - 25 M⊙ progenitor mass and
solar metallicity. A fit over the whole range until 10 Myr shows also a second increase of 53Mn/Mn in the range around 6 Myr matching
recent 60Fe detection in sediments at ANU.
Keywords: AMS; 53Mn; Supernova
Contribution to WWW
eingereichtes Abstract für abgesagte DPG-Frühjahrstagung: https://www.dpg-verhandlungen.de/year/2020/conference/hannover/part/ms/session/12/contribution/4
Development of novel α-CEA target modules (RevTMs) for the switchable RevCAR system
González Soto, K. E.
Cancer is one of the main causes of death and represents a worldwide health problem. Most of the cancer-related deaths are associated with the appearance and progression of a solid tumor. Even though effective conventional treatments exist, they share a common drawback, which is their incapacity to strictly distinguish between malignant and healthy cells. Since it was observed that immune cells are capable to eliminate cancer cells, extensive research has been made to retarget immune cells towards malignant cells without damaging healthy tissue. This type of approach is termed as immunotherapy and involves diverse strategies ranging from the use of Abs to engineered immune cells. One of the most attractive immunotherapeutic strategies is based on the engineering of T cells to express chimeric antigen receptors (CARs), which can recognize specific antigens localized on the surface of cancer cells, leading to an activation of the CAR T cells and a subsequently killing of the malignant cells. Even though CAR technology has shown a strong potential in targeting cancer cells during pre-clinical and clinical studies, numerous clinical trials have also revealed that once they are infused into the patient, the activity of the modified T cells becomes uncontrollable, which represents the main safety problem from the system. For this reason, a novel modular and switchable CAR platform, termed as RevCAR system, was developed in the group of Prof. Bachmann. A crucial element of mentioned system is the design of the RevCAR. In contrast to conventional CARs, RevCARs lack an extracellular binding moiety and comprise only a short peptide epitope instead. Thus, RevCAR T cells are per se inert because they cannot bind to any antigen. Only in the presence of target modules (RevTMs), which bind on the one hand to the peptide epitope of RevCARs and on the other hand simultaneously to tumor targets, RevCAR T cells can be redirected and consequently activated against tumor cells. An attractive tumor-associated antigen (TAA) for the development of immunotherapies is the carcinoembryonic antigen (CEA), because it is highly overexpressed on certain cancer types associated with solid tumor formation, such as breast and lung cancer. In order to show the proof of concept that CEA is an optimal TAA to redirect the RevCAR system, two different formats of RevTMs (scFv- or IgG-based) were produced and tested for their functionality. Here we have shown, that both RevTMs were able to efficiently redirect RevCAR T cells to eliminate CEA-expressing tumor cells in an antigenand epitope-specific as well as TM-dependent manner. Moreover, here, the IgG4-based RevTM worked more efficient than the scFv-based RevTM.
Off-harmonic optical probing of high intensity laser interaction with cryogenic hydrogen jet target
High-intensity short-pulse lasers in the Petawatt regime offer the possibility to study new compact accelerator schemes by utilizing high-density targets for the generation of energetic ion beams. The optimization of the acceleration process demands comprehensive exploration of the plasma dynamics involved, for example via optical probing. In particular, experiments using low density cryogenic hydrogen jet targets with µm-scale transverse size are well suited to deliver new results which can then be compared to predictive particle-in-cell simulations. However, strong plasma self-emission and conversion of the plasma’s drive laser wavelength into its harmonics often masks the interaction region and complicates data analysis. Here, we present a stand-alone probe laser system operating at 1030 nm, far off the plasma’s drive laser wavelength of 800 nm and its implementation into an experiment dedicated to laser-proton acceleration from the hydrogen jet target irradiated by the DRACO PW laser at Helmholtz-Zentrum Dresden – Rossendorf. We show that the plasma self-emission in the probe images is significantly suppressed and we are able to measure the pre-expansion of the target by the DRACO PW laser for intrinsic and for plasma mirror enhanced laser contrast. The influence of the plasma pre-expansion on the measured proton acceleration performance is presented.
Keywords: optical probing; laser; laser particle acceleration
European Advanced Accelerator Concepts Workshop, 15.-20.09.2019, Isola d'Elba, Italy
Antigen-specific redirection of immune effector cells against GD2-expressing tumors
Extensive research in the last decades has revealed the dynamic role of the immune system in surveillance, recognition and elimination of cancer cells. However, resistant variants can rise and overcome these immune responses by various escape mechanisms. Therefore, huge efforts have been invested in developing of immunotherapies that can overcome these hurdles and allow the specific activation and retargeting of immune cells toward tumor cells. Immunotherapy includes diverse strategies ranging from cytokines to antibodies and their derivatives reaching to engineered immune cells.
One of the very promising immunotherapeutic approaches is based on the engineering of T cells to express chimeric antigen receptors (CARs) which can redirect immune cells to specific antigens leading to T cell activation and subsequent killing of target cells. The CAR technology has shown a strong therapeutic potential in targeting of cancer both in preclinical as well as clinical studies, especially with hematological malignancies, which lead to FDA approval of CD19-specific CAR T cells for the treatment of leukemia. Despite the success of CAR T cells, clinical trials have also revealed various toxicities and adverse events that can be life-threatening for patients. Moreover, the CAR technology still faces many hurdles to achieve an effective targeting of solid tumors due to the structure, immunosuppressive microenvironment and heterogeneity of the disease. Therefore, a novel modular and switchable CAR platform, called the UniCAR system, was developed in the group of Prof. Bachmann in order to address these obstacles. The UniCAR system consists of UniCAR T cells that cannot bind surface antigens. Instead, UniCARs recognize an epitope (E5B9) which is derived from the nuclear protein La-SS/B. Therefore, UniCAR T cells can only be redirected via target modules (TMs) that have the E5B9 tag on one hand and an antigen-binding domain on the other hand. These TMs provide a bridge with tumor cells that allow the activation of UniCAR T cells. Once these TMs are eliminated, the UniCAR T cells can no more be activated, and thus they are switched off. This approach provides not only a safety switch but also a flexible platform for multi-targeting of diverse antigens by using various TMs with different antigen specificities. Alternatively, the UniCAR system can be applied on NK cells or NK cell lines, which have a natural anti-tumor response. Cell lines like NK-92 are of especial interest because they can be used allogenically, and thus provide an off-the-shelf therapy that might reduce the cost and time of therapy development.
For my thesis work, disialoganglioside GD2 was selected as a target for the UniCAR system. GD2 is overexpressed on many tumors including neuroblastoma, Ewing’s sarcoma, melanoma, osteosarcoma and others. In fact, GD2 is considered as one of the priority antigens to be targeted for cancer therapy according to a pilot project of the national cancer institute. Moreover, targeting GD2 with CAR T cells has shown very positive clinical outcome in previously published clinical trials. However, as other tumor-associated antigens, GD2 has also some limited expression on normal tissues including some regions of the central nervous system and peripheral nerves. Therefore, using a safety switch like the UniCAR system emerges as a necessary step to assure better controlling of any on-target/off-tumor side effects.
Driven by these facts, several formats of anti-GD2 TMs were developed in order to redirect UniCAR T cells to GD2-expressing tumors. Three TMs were designed based on a single chain fragment variable (scFv) connected to the E5B9 epitope. However, they differed in the orientation of the variable light and variable heavy chain domains and their linker components in order to find the best functional conformation. In vitro functional assays showed that all of the three TMs were able to redirect UniCAR T cells toward tumor cells leading to efficient tumor cell killing and release of cytokines in an antigen-specific and TM-dependent manner. Furthermore, the TMs showed dose-dependent killing with half-maximal effective concentration (EC50) in the picomolar range. As all the TM formats showed comparable results in vitro, further in vivo studies were restricted to one TM. This anti-GD2 TM was able to activate UniCAR T cells to eradicate GD2-positive tumor cells in experimental mice. Furthermore, the TM was modified and radiolabeled with 64Cu, in order to investigate its pharmacokinetic properties and biodistribution in tumor-bearing mice. PET analysis of the radiolabeled anti-GD2 TM showed enrichment in the GD2-expressing tumors with blood elimination half-life of less than one hour, which makes it a suitable key for a fast safety switch of UniCAR T cells.
In contrast to UniCAR T cells, the UniCAR NK-92 cell line provides an-off-the shelf therapy that can be expanded for allogenic use. Since these cells are usually irradiated before infusion into patients, their life-span as well as the possibility of side effects is reduced. Therefore, we have further created an IgG4-based anti-GD2 TM with an extended half-life that fits to the life-span of irradiated NK-92 cells. PET imaging of the radiolabeled IgG4-based TM showed an increase in the half-life of about 24 folds in comparison to the scFv TM format. Further testing has shown that UniCAR NK-92 cells are functional with both scFv- and IgG4-based TM formats leading to specific killing of GD2-expressing tumor cells as well as secretion of pro-inflammatory cytokines in vitro. In addition, UniCAR NK-92 showed specific killing of tumor cells in vivo when combined with the anti-GD2 TM.
In summary, we have shown that the UniCAR system can be used to redirect both T cells and NK-92 cells against GD2-expressing tumors in vitro as well as in vivo in an antigen-specific and TM-dependent manner. The UniCAR system allows an on/off safety switch as well as fine controlling of the activity of UniCAR T/NK-92 cells via titration (dosing) of the anti-GD2 TMs. Furthermore, it provides a flexible platform that allows the use of several antibody formats for an effective and safe targeting of cancer.
Off-harmonic optical probing of high intensity laser interaction with hydrogen targets using a stand-alone probe laser system
The development of high-intensity short-pulse lasers in the Petawatt regime offers the possibility to design new compact accelerator schemes by utilizing high-density targets for the generation of ion beams with multiple 10 MeV energy per nucleon. The optimization of the acceleration process demands comprehensive exploration of the plasma dynamics involved, for example via spatially and temporally resolved optical probing. Experimental results can then be compared to numerical particle-in-cell simulations, which is particularly sensible in the case of cryogenic hydrogen jet targets. However, strong plasma self-emission and conversion of the plasma’s drive laser wavelength into its harmonics often masks the interaction region and interferes with the data analysis. Recently, the development of a stand-alone and synchronized probe laser system for off-harmonic probing at the DRACO laser operated at the Helmholtz-Zentrum Dresden–Rossendorf showed promising performance.
Here, we present an updated stand-alone probe laser system applying a compact CPA system based on a synchronized fs mode-locked oscillator operating at 1030 nm, far off the plasma’s drive laser wavelength of 800 nm. A chirped volume Bragg grating (Optigrate Corp) is used as a hybrid stretcher and compressor unit. The system delivers 160 fs pulses with a maximum energy of 0.9 mJ. By deploying the upgraded probe laser system in the laser-proton acceleration experiment with the renewable cryogenic hydrogen jet target, the plasma self-emission could be significantly suppressed while studying the temporal evolution of the expanding plasma jet. Recorded probe images resemble those of z-pinch experiments with metal wires and indicate a sausage-like instability along the jet axis, which will be discussed.
Keywords: optical probing; laser; laser particle acceleration
SPIE Optics + Optoelectronics 2019, 01.-04.04.2019, Prague, Czech Republic
Stand-alone laser system for off-harmonic optical probing of high intensity laser interaction with cryogenic hydrogen jet targets
The availability of high-intensity short-pulse lasers in the Peta-Watt regime drives the development of new and compact accelerator schemes like for example the generation of multiple 10 MeV proton beams from high-density targets. To optimize the acceleration performance and to pave the way towards medical applications of these particle beams both target and diagnostic development are of great importance. Particularly cryogenic hydrogen jet-targets offer the benefit of being debris-free and capable of high-repetition rate applications. Together with spatially and temporally resolved optical probing techniques this target is most suitable for a comparison to numerical particle-in-cell simulations. However, the strong plasma self-emission often masks the laser-target interaction point and thus complicates the data analysis. Recently, the development of a synchronized stand-alone probe-laser-system operating off the harmonics of the driver laser showed promising performance.
Here we show the performance of an upgraded probe-laser-system operating at a central wavelength of 1030nm far off the fundamental wavelength of the drive laser at 800nm. It consists of a synchronized fs-oscillator and a novel and robust CPA system based on a chirped volume Bragg grating as a hybrid stretcher and compressor unit, chirped mirrors for GDD compensation and a regenerative amplifier with Yb.CaF2 as laser medium. The system delivers 160fs pulse duration together with 0.9mJ energy at a repetition rate of 200Hz.
The application of the upgraded probe-laser-system in an experimental campaign dedicated to laser-proton acceleration together with cryogenic hydrogen jet-targets showed a significant improvement of imaging quality for the laser-target interaction concerning the plasmas self-emission. The recorded probe-images resemble those of z-pinch experiments with metal wires and indicate a sausage-like instability along the hydrogen jet axis.
Keywords: optical probing; laser; particle acceleration
DPG Frühjahrstagung, 17.-22.03.2019, München, Deutschland
Introducing a novel switchable CAR platform with reduced CAR size for immunotherapy of tumors
Recently the use of chimeric antigen receptor (CAR) modified T cells in the immunotherapy of tumors has become a promising approach. CAR T cells are able to recognize tumor-associated antigens (TAAs) in a major histocompatibility-complex (MHC)-independent manner. Although highly efficient, the inability to regulate the activity of CAR T cells can cause severe side effects and thus needs to be considered in future developments. Here, we introduce the RevCAR system – a novel switchable modular universal CAR system having a minimal size to overcome the obstacles of conventional CAR therapy.
In order to improve the controllability of CAR T cells a modular CAR system, which allows switching the activity of CAR T cells repeatedly “ON” and “OFF”, was generated. Furthermore, to avoid unspecific side effects and minimize tonic signaling of conventional CAR T cells, the extracellular single chain variable fragment (scFv) was removed. Thus, resulting RevCARs have a smaller size allowing “gated” targeting strategies, e.g. by facilitating simultaneous transduction of two independent CARs with different specificities and split motifs, which could further improve the safety of CAR T cells.
3. Materials & methods
In order to reduce the size of the artificial receptor the original idea was to replace the extracellular scFv domain of a conventional CAR with a small peptide epitope and to engage the resulting RevCAR
T cell via a bispecific target module which we termed RevTM. For proof of concept two small peptide epitopes were selected and the respective RevCARs constructed. In addition, a series of different RevTMs was generated. On the one hand the RevTM recognizes one of the two peptide epitopes on the other hand the RevTM can be directed to any potential TAA.
Until now a series of RevTMs was constructed and functionally analyzed. RevCAR T cells armed via the respective RevTM were able to efficiently lyse their respective target cells in a peptide epitope and target specific, as well as target module dependent manner. These data are supported by the analysis of cytokine secretion from RevCAR T cells which was only observed in the presence of both target cells and the respective RevTM.
Taken together these results demonstrate the high anti-tumor efficiency of the novel RevCAR platform which is characterized by a small size, an improved safety, easy controllability as well as high flexibility.
Abstract in refereed journal
European Journal of Immunology 49(2019), 266-267
Annual Meeting of the German Society for Immunology (DGfI 2019), 10.-13.09.2019, München, Deutschland
- Final Draft PDF 314 kB Secondary publication
Convective and Surface Tension Sub-Filter Scale Models
Industrial applications feature a huge variety of different flow patterns, such as bubbly flow, slug flow or annular flow. Thereby the issue of a big range of different physical scales is involved. With the objective of reproduction of occurring phenomena with one single multifluid solver, we present an Euler-Euler-approach, which combines a number of different methods for treatment of the partial aspects. The implementation into OpenFOAM is always with focus on sustainable research. A segregated approach is used for treatment of the phase momentum equations, phase fraction equations and the pressure equation, featuring a consistent momentum interpolation scheme (Cubero et al., 2014). To fulfill the kinematic condition at resolved interfaces between different continuous phases, the latter may be coupled by an isotropic drag (Strubelj and Tiselj, 2011). In this case, the immensely strong phase coupling requires an adapted numerical method. The overall objective is to take interactions between the all different aspects, such as disperse phases, resolved interfaces and turbulence with effects on momentum and mass transfer into account.
Seminar des Instituts für Mathematik und Rechneranwendungen der Universität der Bundeswehr München, 05.11.2019, München, Deutschland
(+)-[18F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand – Results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer’s disease and healthy controls
Tiepolt, S.; Becker, G.-A.; Wilke, S.; Cecchin, D.; Rullmann, M.; Meyer, P. M.; Barthel, H.; Hesse, S.; Patt, M.; Luthardt, J.; Wagenknecht, G.; Sattler, B.; Deuther-Conrad, W.; Ludwig, F.-A.; Fischer, S.; Gertz, H.-J.; Smits, R.; Hoepping, A.; Steinbach, J.; Brust, P.; Sabri, O.
The cerebral cholinergic system is involved in several cognitive processes and neuropsychiatric 2 diseases. For research purposes and later on in routine clinical settings new PET radioligands with more favorable characteristics than the established 3-pyridylether derivatives with their slow kinetics are necessary. Here we present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[18F]Flubatine. Primary aim of this study was to develop a kinetic modeling-based approach to quantify the α4β2 nAChR availability in the human brain and to compare respective data of healthy controls (HCs) with those of patients with Alzheimer’s disease (AD). Secondary aims were to investigate whether (+)-[18F]Flubatine binding was correlated to cognitive test data or β-amyloid radiotracer accumulation. Furthermore, the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding was investigated. We examined 11 non-smoking HCs and 9 non-smoking patients with mild AD without anti-dementive drugs. Prior to (+)-[18F]Flubatine PET, all subjects underwent an extensive neuropsychological testing and a β-amyloid [11C]PiB PET/MRI examination. To evaluate the (+)-[18F]Flubatine PET data, we used full kinetic modeling (one and two tissue compartment 16 modeling (1TCM and 2TCM)) and regional as well as voxel-based analyses. 270 min p.i., the unchanged parent compound in arterial blood amounted to 97±2%. As revealed by regional analysis, (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in the bilateral mesial temporal cortex in AD patients compared to HCs (right: AD: 10.6±1.1 vs HC: 11.6±1.4, p=0.049; left: AD: 11.0±1.1 vs HCs:12.2±1.8, p=0.046). Voxel-based analysis detected further clusters of reduced (+)-[18F]Flubatine in left precuneus/posterior cingulate cortex, right superior temporal and left middle temporal cortex (k>30, p<0.001). PVE correction revealed an increase of regional (+)-[18F]Flubatine binding of approximately 15% but also an increase of the standard deviation of 0.4-70% resulting in a loss of statistical significances. Thus, we also estimated the cortical thickness to investigate whether cortical atrophy significantly affects the regional (+)-[18F]Flubatine binding. Here, we found that mesial temporal cortical thickness did not correlate with (+)-[18F]Flubatine binding (right: r=0.10, p=0.69; left: r=0.17, p=0.48). Using a reference region (occipital cortex), also the right parietal cortex showed reduced relative (+)-[18F]Flubatine binding in AD patients compared to HCs (1.1±0.1 vs. 1.2±0.1, p=0.033). Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in left anterior cingulate cortex, right posterior cingulate cortex and right parietal cortex (r>0.5, p<0.05 each). In the AD patients, (+)-[18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions, whereas in HCs a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No serious adverse events were registered, and seven adverse events which were not related to the investigational product. Taken together, (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling of the PET data can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences without the use of a reference region. However, the use of the occipital cortex as reference region increased the sensitivity. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated a connection between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR-targeting PET ligand in further clinical trials.
Keywords: (+)-[18F]Flubatine; α4β2 nicotinic acetylcholine receptors; human brain; kinetic modeling; PET; (+)-[18F]NCFHEB
European Journal of Nuclear Medicine and Molecular Imaging 48(2021), 731-746
Online First (2020) DOI: 10.1007/s00259-020-05029-w
A-Posteriori Assessment of Sub-Filter Scale Models for Turbulence-Interface Interaction with the Two-Fluid Formulation Considering a Single Rising Gas Bubble in Liquid
Gas-liquid flows are of great importance for a large number of different industrial applications, e.g. in energy sector or metal processing industry. From there arises a strong need for numerical tools, which help to predict dynamics of two-phase flows in technical facilities with high predictive accuracy, reasonable computational expense and without any need for initial knowledge of the present flow regime. A big challenge in investigations of such problems is the large range of interfacial and turbulent scales, which need to be accounted for in numerical simulations. A typical approach to capture all these dynamics and their interactions are multi-scale multi-regime methods, which make use of coupling of different individual modeling concepts.
The overall aim is to adopt the hybrid approach of H ̈ ansch et al. (2012), which combines an Eulerian-Eulerian approach with a volume-of-fluid(VOF)-like method in a two-fluid model in order to represent interfacial structures on subgrid-scale and on grid-scale, respectively. In situations, where transitions between different morphologies occur, interfacial structures appear to be too large for an Eulerian-Eulerian model approach and, at the same time, too small for the flow dynamics to be fully resolved in a VOF-like model. In other words, in the range of mesh scale and slightly above, interfacial and turbulent structures need to be simulated in an under-resolved manner. For this to deliver physically reasonable results, modeling of subgrid-scale (SGS) dynamics becomes necessary.
- Grobstruktursimulation blasenbehafteter Strömungen mittels … (Id 32586) references this (Id 30205) publication
Contribution to proceedings
Direct and Large Eddy Simulation 12 (DLES12), 05.-07.06.2019, Madrid, Spanien
ERCOFTAC Series: Direct and Large-Eddy Simulation XII, Cham, Switzerland: Springer, 978-3-030-42821-1, 167-173
Direct and Large Eddy Simulation 12 (DLES12), 05.-07.06.2019, Madrid, Spanien
On the enstrophy in a precessing cylinder
Within the project DRESDYN (DREsden Sodium facility for DYNnamo and thermohy-
draulic studies) a precession driven a fluid flow of liquid sodium will be examined with regard
to the possibility of serving as source for magnetic field generation. Hydrodynamic studies
and simulations are essential to understand the behaviour of the fluid flow. Here we present
the direct numerical simulations of a fluid flow forced by precession conducted in a cylindrical
domain, with the focus on the relation between dissipation and enstrophy.
Keywords: Precessing Cylinder; enstrophy; flow field
Invited lecture (Conferences)
9th European Postgraduate Fluid Dynamics Conference, 16.-19.07.2019, Ilmenau, Germany
The Dresdyn Precession Dynamo Experiment
In the most ambitious experiment of DRESDYN (DREsden Sodium facility
for DYNnamo and thermohydraulic studies) a fluid flow of liquid sodium, solely driven
by precession, will be considered as a possible source for magnetic field generation. Here,
after the description of the experimental facility, we are going to present the results (in
particular the hydrodynamic ones) from the direct numerical simulation conducted in a
cylindrical domain. We will discuss the dynamics of the system and show that the m = 1
Kelvin mode is crucial for the dynamo action. The second part will be dedicated to the
influence of the nutation angle; finally we will quantify the dissipation and the role of
turbulent fluctuations on the flow.
Keywords: cylinder; dissipation; dynamo; precession; turbulence
Contribution to proceedings
11 th PAMIR International Conference - Fundamental and Applied MHD, 01.-05.07.2019, Reims, France
Invited lecture (Conferences)
11 th PAMIR International Conference - Fundamental and Applied MHD, 01.07.2019, Reims, France
Start-to-end simulations of L|PWFA hybrid accelerator experiments using PIConGPU
Pausch, R.; Debus, A.; Steiniger, K.; Garten, M.; Hübl, A.; Widera, R.; Kurz, T.; Schöbel, S.; Couperus Cabadağ, J. P.; Chang, Y.-Y.; Köhler, A.; Zarini, O.; Heinemann, T.; Gilljohann, M. F.; Ding, H.; Götzfried, J.; Döpp, A.; Kononenko, O.; Raj, G.; Martines De La Ossa, A.; Assmann, R.; Hidding, B.; Karsch, S.; Code, S.; Irman, A.; Schramm, U.; Bussmann, M.
The poster gives an overview of the LPWFA experimental setup and explains in detail the accompanying simulation campaign.
Keywords: LPWFA; hybrid; PIConGPU; ISAAC; alpaka
CASUS Eröffnungsworkshop, 26.-28.08.2019, Görlitz, Deutschland
Current status of the L|PWFA start-to-end simulations using PIConGPU
A summary of the LPWFA simulations of the last half year as performed within the hybrid collaboration.
Keywords: PIConGPU; LPWFA; hybrid
LPWFA hybrid-collaboration meeting, 04.-05.07.2019, Glasgow, United Kingdom
Ultra-intense laser pulse characterization using ponderomotive electron scattering.
We present a new analytical solution for the equation of motion of relativistic electrons in the focus of a high-intensity laser pulse. We approximate the electron's transverse dynamics in the averaged field of a long laser pulse focused to a Gaussian transverse profile. The resultant ponderomotive scattering is found to feature an upper boundary of the electrons' scattering angles, depending on the laser parameters and the electrons' initial state of motion. In particular, we demonstrate the angles into which the electrons are scattered by the laser scale as a simple relation of their initial energy to the laser's amplitude. We find two regimes to be distinguished in which either the laser's focusing or peak power are the main drivers of ponderomotive scattering. Based on this result, we demonstrate how the intensity of a laser pulse can be determined from a ring-shaped pattern in the spatial distribution of a high-energy electron beam scattered from the laser. We confirm our analysis by means of detailed relativistic test particle simulations of the electrons' averaged ponderomotive dynamics in the full electromagnetic fields of the focused laser pulse.
New Journal of Physics 21(2019), 123028
Characterization of laser-driven proton acceleration from water microdroplets
We report on a proton acceleration experiment in which high-intensity laser pulses with a wavelength of 0.4 μm and with varying temporal intensity contrast have been used to irradiate water droplets of 20 μm diameter. Such droplets are a reliable and easy-to-implement type of target for proton acceleration experiments with the potential to be used at very high repetition rates. We have investigated the influence of the laser’s angle of incidence by moving the droplet along the laser polarization axis. This position, which is coupled with the angle of incidence, has a crucial impact on the maximum proton energy. Central irradiation leads to an inefficient coupling of the laser energy into hot electrons, resulting in a low maximum proton energy. The introduction of a controlled pre-pulse produces an enhancement of hot electron generation in this geometry and therefore higher proton energies. However, two-dimensional particle-in-cell simulations support our experimental results confirming, that even slightly higher proton energies are achieved under grazing laser incidence when no additional pre-plasma is present. Illuminating a droplet under grazing incidence generates a stream of hot electrons that flows along the droplet’s surface due to self-generated electric and magnetic fields and ultimately generates a strong electric field responsible for proton acceleration. The interaction conditions were monitored with the help of an ultra-short optical probe laser, with which the plasma expansion could be observed.
Scientific Reports 9(2019), 17169
Standing inertial waves, energy scaling and dissipation in precession driven flows
A precession dynamo experiment is currently under construction at
Helmholtz-Zentrum Dresden-Rossendorf (HZDR). The experiment is
motivated by the question whether the geodynamo or the ancient lunar
dynamo were powered by a flow driven by precession instead of
or in addition to convection. In the present study we address related
numerical simulations in order to characterize the hydrodynamic flow
field and to make energetic estimations that allow conclusions on the
global power balance.
Simulations of precessing fluids in cylindrical geometry show that
precession is an efficient mechanism to drive substantial flows even
on the lab scale. Using the time-averaged flow field obtained in these
simulations, kinematic dynamo models exhibit dynamo action at
parameters that are well within the range of the planned dynamo
experiment. Our analysis further shows that the standing inertial
wave directly excited by precession is responsible for the magnetic
field excitation when the forcing is sufficiently strong, so that
nonlinear interactions modify the flow and contributions beyond the
resonant Kelvin mode become important. This requires large precession
ratios with the Poincare number (the ratio of precession
frequency to rotation frequency) above Po = 0.10. At this
value we observe an abrupt transition of the flow into a turbulent
behavior with large-scale flow structures becoming less significant.
Our simulations give a detailed characterization of the corresponding
transition. The scaling of global quantities, like flow amplitudes and
energies as well as the laminar and the turbulent dissipation are used
to constrain the energetics of the magnetic field generation and to
predict the most promising parameter regimes suitable for dynamo
action including the specific magnetic field pattern that may emerge
in the planned dynamo experiment.
Keywords: Dynamo; DRESDYN; Precession
AGU Fall Meeting, 08.-13.12.2019, San Francisco, USA
Synchronization in mean field dynamo models
Synchronization is a fundamental phenomenon in nonlinear dynamical systems.
In my presentation I will refer to essential features of synchronized
systems with focus on a kinematic dynamo model driven by two
counter-rotating disks including weak periodic perturbations. Similar
concepts can be used to explain the behavior of triadic resonances in a
precession driven flow, which may be seen as a precursor for the
transition into a turbulent regime found at a critical precession ratio
in the DRESDYN water experiment. Finally, I show the connection to the
synchronized solar dynamo model presented by Frank Stefani, where the
magnetic field frequencies are determined by the tidal forces caused by
planets surrounding the sun.
Keywords: Dynamo; Synchronization
Dynamo Thinkshop, 25.-26.12.2019, Rom, Italien
Inverse Problems in (nonlinear) Magnetohydrodynamics
Modal acoustic velocimetry and time-of-flight tomography require
inversion of measurement data for determination of 3D velocity fields.
Another example is the Inductive flow tomography that allows the estimatation
of flow structures in an electrically conducting fluid impacted by an imposed
Symposium "Domain Coupling with Workflow-supported Algorithms of Artificial Intelligence", 29.05.2019, Berlin, Deutschland
Euler-Euler Multiphase Flow Simulation @ HZDR
Research on multiphase flows has a long history at Helmholtz-Zentrum Dresden - Rossendorf. Concerning simulations we focus on the Euler-Euler method, which facilitates CFD simulations on the scale of technical equipment by applying the two-fluid framework of interpenetrating continua. Since phenomena occurring on the scale of individual bubbles or groups thereof are not resolved in this approach, accurate numerical predictions rely on suitable closure relations describing the physics of these small-scale phenomena. Development and validation of such closure relations are a core focus of our research.
A brief general overview of topics and methods will be given, followed by a collection of specific application examples. The latter center around dispersed multiphase flows in different types of equipment commonly encountered in chemical engineering, minerals processing, and biotechnology. The fluid dynamics of bubbly flow are covered in greater detail highlighting the modeling of bubble forces, bubble-induced turbulence as well as bubble-coalescence and breakup. Less comprehensive results are shown for reactive mass-transfer and particulate flows.
Keywords: disperse gas-liquid multiphase flow; Euler-Euler two-fluid model; fluid dynamics; mass transfer; chemical reaction; CFD simulation; validation
Institute Seminar, 13.12.2019, Magdeburg, Deutschland
Euler-Euler Simulation of Bubbly Flow in Stirred Tanks
Rzehak, R.; Shi, P.
Aerated stirred tanks are frequently used equipment in industries ranging from chemical engineering and biotechnology to minerals processing. In principle, CFD simulation of such equipment on industrial scales is feasible within the Euler-Euler framework of interpenetrating continua. Practical application, however, requires suitable closure models to account for phenomena on the scale of individual bubbles, which are not resolved in this approach. Validation of such models is the purpose of the present contribution.
Keywords: aerated stirred tanks; dispersed gas-liquid multiphase flow; Euler-Euler two-fluid model; closure relations; Reynolds-stress turbulence model; CFD simulation
ECCE12 & ECAB5, 15.-19.09.2019, Florence, Italy
TEM investigation of Compact Tellurium Thin Films with Bismut Atomic Doping
Damm, C.; Guodong, L.; Hübner, R.; Nielsch, K.
Compact tellurium (Te) thin films show important applications in micro-thermoelectric modules, which are able to convert waste heat to electrical energy (μTEG) or vice versa to use electricity to generate cooling (μTEC). The as-fabricated μTECs, which are based on electrochemically deposited n-type Bi2(TexSe1-x)3 (in short BiTeSe) and p-type tellurium, demonstrate a rapid response time of 1ms, a high cycling reliability of up to 10 million cycles and a long-term cooling stability of more than 1 month at constant electric current. However, a mismatch of electrical conductivity between pure Te and BiTeSe often leads to some difficulties in the geometry design of micro-thermoelectric modules. In order to enhance the electrical property of Te, we have introduced an atomic bismuth (Bi) doping.
In this report, we have performed transmission electron microscopy (TEM, FEI Tecnai G2/ 200 kV) analysis to observe the presence and distribution of Bi within Te. To this end, cross-sectional TEM specimens were prepared using the Focused Ion Beam technique (FIB, FEI Helios NanoLab 600i). The Bi-doped Te samples have a columnar grain structure. Selected-area electron diffraction proves the presence of crystalline Te. Results of Nanodiffraction in numerous areas also suggest Te (hexagonal, space group 152, a = b = 0,4458 nm, c = 0,5925 nm, α = ß = 90°, γ = 120°) but could be explained with Bi (rhomboedral, space group 166, a = b = 0,4550 nm, c = 1,1850 nm, α= ß = 90°, γ = 120°), too. Unfortunately, the geometry of the Bi and Te unit cells differ only in the length of the c-axis. In addition, HRTEM images show lattice fringes, which could belong to Bi or Te. To unambiguously distinguish between both elements, chemical analysis is necessary.
Performing energy-dispersive X-ray spectroscopy (EDXS) analysis with a conventional Si(Li) detector, no Bi counts appear in the EDX spectra during reasonable measuring times of several minutes. To finally get the distribution of Bi in the Te matrix, we employed a FEI Talos F200X microscope operated at 200 kV and equipped with an X-FEG electron source and a Super-X EDX detector system and performed spectrum imaging analysis based on EDXS.
Microscopy Conference MC 2019, 01.-05.09.2019, Berlin, Germany
Investigation on the working mechanism of the nitrile based sulfide collector Tecflote
Tecflote is a new group of nitrile-based collectors for sulphide flotation. The fact that it is insoluble in water results in some interesting implications for its actual working mechanism. It can be assumed that the Tecflote-molecules are adsorbed in the air water interface having first contact with the mineral surface during the particle bubble collision rather than conventional theories where particles are hydrophobized within the pulp in a conditioning step. Therefore, the adsorption of Tecflote and the spreading of the three-phase contact line between the mineral surface and the air bubble must be related to each other. Different investigations including contact angle measurements and AFM studies are conducted to obtain a better understanding of the working mechanism of Tecflote. Due to the insoluble character, the Langmuir-Blodgett technique is used to investigate the behaviour of Tecflote in the air-water interface and to deposit layers of Tecflote on mineral substrates for the above-mentioned studies.
Flotation '19, 11.-14.11.2019, Kapstadt, Südafrika
A Recirculation Cell Approach for Hydrodynamic and Mass Transfer Modeling in Bubble Columns with and without Internals
An advanced recirculation cell model is proposed, which describes fluid dynamics and mass transfer in bubble columns with and without internals. The new model incorporates the cell approach of Shimizu et al. [Chem. Eng. J. 2000, 78, 21-28.] with latest breakup and coalescence kernels. Additionally, the gas flow structure is divided according to the two-bubble class assignment with fast-rising large bubbles in the column center and descending small bubbles near the wall following the liquid circulation pattern within the column’s cross-section. The effect of internals is considered dividing the column further into ‘sub-columns’ derived from the internals’ radial profile, which physically refines the liquid circulation pattern. The model was validated with experimental data of Möller et al. [Chem. Eng. Sci. 2018, 179,265-283; Chem. Eng. Res. Des. 2018, 134; Chem. Eng. Sci. 2019] for narrow (0.1 m diameter) and pilot-scale (0.39 m diameter) columns, respectively, with and without internals operated up to the well-developed churn-turbulent flow regime. Predictions for bubble size distribution, total gas holdup, Sauter mean diameter as well as interfacial area and volumetric mass transfer coefficients agree well with the experiments.
Keywords: Bubble column; tube bundle internals; recirculation cell model; two-bubble class approach; hydrodynamics; mass transfer
Chemical Engineering Journal 383(2020), 123197
Online First (2019) DOI: 10.1016/j.cej.2019.123197
- Final Draft PDF 1,6 MB Secondary publication
WKB approach to pair creation in spacetime-dependent fields: The case of a spacetime-dependent mass
Besides tunneling in static potential landscapes, for example, the Wentzel-Kramers-Brillouin (WKB) approach is a powerful nonperturbative approximation tool to study particle creation due to time-dependent background fields, such as cosmological particle production or the Sauter-Schwinger effect, i.e., electron-positron pair creation in a strong electric field. However, our understanding of particle creation processes in background fields depending on both space and time is rather incomplete. In order to venture into this direction, we propose a generalization of the WKB method to truly spacetime-dependent fields and apply it to the case of a spacetime-dependent mass.
Physical Review D 99(2019)12, 125014
Contribution to WWW
Boltzmann relaxation dynamics in the strongly interacting Fermi-Hubbard model
Via the hierarchy of correlations, we study the Mott insulator phase of the Fermi-Hubbard model in the limit of strong interactions and derive a quantum Boltzmann equation describing its relaxation dynamics. In stark contrast to the weakly interacting case, we find that the scattering cross sections strongly depend on the momenta of the colliding quasi-particles and holes. Therefore, the relaxation towards equilibrium crucially depends on the spectrum of excitations. For example, for particle-hole excitations directly at the minimum of the (direct) Mott gap, the scattering cross sections vanish such that these excitations can have a very long life-time.
Physical Review A 100(2019)5, 053617
Contribution to WWW
The impact of mineralogy on processing for recovery of chromite and PGE in the Bushveld Complex, South Africa
The Lower and Middle Group (LG and MG) chromitites of the Bushveld Complex in South Africa are the source of a very large portion of the global chrome supply. The recovery of platinum group elements and base metals (Ni, Cu) as by-products has the potential to add value to these chrome resources. Yet, the effectiveness of chromite and platinum-group element beneficiation circuits is highly sensitive to variations in feed composition. Mineral assemblages have been noted to be affected by surficial weathering (down to 50 m) and hydrothermal alteration. Of particular relevance is the abundance of alteration silicates, the prevailing base metal sulphides (BMS) and platinum group mineral (PGM) assemblages and mineral association which have a significant impact on recoveries and concentrate grade. The goal of this particular case study was to evaluate the potential recoverability of platinum group elements (PGE) as a by-product during chromite production in the Thaba Mine. As shown by a lot of studies, only a very minor amount of the economically important 3E (Pt,Pd,Rh) is enclosed in chromite and will therefore report to the chromite concentrate. On the other hand, the 6E (Pt, Pd, Rh, Ru, Ir and Au) grades of the mined chromitites are usually below 2 g/t and the feasibility of an additional PGE processing plant will be challenging. Therefore, a versatile and flexible geometallurgical framework is needed to identify potential PGE targets within the mine and to predict the recoverability of PGE in the ore. To extract a maximum of information at a minimal cost and material use, the framework proposed iterates between analytical work and statistical/ mathematical modelling.
Here, we focus on the metallurgical test work results of unweathered LG and MG chromitites. More than 100 different diamond drill core intersections of chromitite seams were used as sample material and analyzed by automated scanning electron-based image analysis. Several properties of each sample were fed into a statistical unsupervised classification scheme to create seven mineralogically distinct clusters for a subsequent metallurgical test work at Mintek. Composited batch samples were milled and fed to a shaking table to separate the chromite as efficiently as possible. Tailings were milled to 80 % < 75 µm, sampled and fed to flotation cells. The tailings of the rougher circuit were discharged and the rougher concentrate was subsequently fed to a cleaner flotation stage. Finally, the cleaner concentrate was sampled and chemically analyzed. Batch sample results display rather homogeneous shaking table feed 3E grades, ranging from 0.43 to 0.69 ppm, while Cr2O3 concentrations display a larger variability, ranging from 35 wt% to 42 wt%. Flotation feed grades range from 0.75 to 1.96 ppm. Cleaner flotation concentrates display grades between ca. 4 ppm and 16 ppm, resulting in upgrading factors between 2 and 11. Overall 3E recovery is between 25 and above 40 %. One reason for these PGE losses could be either large and liberated PGM grains or BMS agglomerates associated with PGM and/or PGE, which would go with the chromite concentrate. To reduce losses at the chromite concentration stage a possible PGM removal upfront with coarse flotation should be considered. Secondly, creating flotation reagent regimes and increasing residence time of the ore in the flotation cells to handle complex PGM assemblages (PGE-alloys and –sulpharsenides) will increase the flotation performance. To further increase the recovery, new flotation technology for better mineral surface cleaning may promote flotation of liberated PGM, as well as increasing liberation (e.g. Mach reactor).
Tagung Aufbereitung und Recycling, 07.-08.11.2019, Freiberg, Deutschland
Highly sensitive ²⁶Al measurements assisted by ILIAMS
The higher ion source output from Al2O3 for AlO− compared to Al− can improve the sensitivity of 26Al AMS measurements. One obstacle is the more complicated isobar suppression after AlO− extraction: For the metallic Al anion the 26Mg background is suppressed in the ion scource. With ion-laser interaction mass spectrometry (ILIAMS), however, the 26Mg isobar can also be completely suppressed for extracted AlO− ions. This now allows the use of the more prolific AlO− beam at facilities with terminal voltages <10 MV.
At the 3MV Vienna Environmental Research Accelerator (VERA) routine ILIAMS assisted AMS measurements of 26Al are performed utilizing AlO− and charge states 2+ and 3+ on the high-energy (HE) side of the spectrometer. Tests of Al2O3 mixtures with different metals were conducted to achieve the optimal generation of AlO− currents.
Admixtures of Cu or Ag powder showed good results but were surpassed by mixing Al2O3 with Fe powder. In addition, results of first experiments will be presented regarding the utilization of ILIAMS assisted 26Al measurements with lower terminal voltages and using the 1+ charge state on the HE side.
Keywords: Accelerator Mass Spectrometry and Applications
Contribution to WWW
eingereichtes Abstract für abgesagte DPG-Frühjahrstagung: https://www.dpg-verhandlungen.de/year/2020/conference/hannover/part/ms/session/8/contribution/3
From Ore to Metal - Advanced Materials Characterisation by Automated Mineralogy
‘Automated Mineralogy’ terms an analytical method that is based on a combination of scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). We suggest to use the term ‘Automated Materials Characterisation’ instead in certain cases, since not only minerals but other solid substances can be characterised by this method. The range of solid natural and artificial materials that has been investigated includes minerals, ores, rocks, mineral beneficiation products and tailings, metals, alloys, slags, construction materials, ceramics, glasses as well as recycling and semiconductor materials and even extraterrestrial materials.
Automated mineralogical investigations provide the unique opportunity to place quantitative constraints on a multitude of parameters tangible for the development and critical evaluation of beneficiation test work. This includes modal mineralogy, calculated elemental content, elemental distributions, mineral associations, particle and mineral size distributions, particle density distributions as well as liberation . Sample overview images (‘mineral maps’) and images of specific mineral groups can also be extracted from the analysis data.
Of particular value is Automated Mineralogy in the field of processing of mineral raw materials. Here, the analyses generate an improved material understanding and are used for evaluation and optimisation of mineral beneficiation processes. Application leads to the reduction of raw material losses coupled with an increased resource and energy efficiency, and thus higher revenue for the operation. Recent research has shown that automated mineralogy data can be used to establish particle-based grade-recovery curves for minerals and elements from feed compositions – and expand the assessment of process efficiencies to include particle distribution probabilities.
The value of Automated Mineralogy is widely recognized in the minerals industry. Yet, its application is most widespread in the characterization of noble (Au, PGE) and base metal (especially Cu, but also Ni) ores and processing streams. The two case studies presented here for Li and Co ores serve to illustrate the potential of Automated Mineralogy during the beneficiation of minor commodities (such as Li) and beneficiation products, including by-products (such as Co). Automated Mineralogy is found to be an analytical method suitable to provide robust quantitative mineralogical data on very complex raw materials; current research extends its application to the characterization of recycling materials. The method is already very well established and an essential part of most studies in the field of processing of primary raw materials, whereas in the case of recycling raw materials only a few sample studies indicate the potential of the method.
- World of Mining 71(2019)5, 283-291
An open source platform for predictive geometallurgy
Geometallurgy (the science of predicting the behaviour of ores along the value chain on the basis of their geoscientific characteristics) has barely moved beyond process mineralogy studies. These studies typically describe the mineralogical and microstructural characteristics of pristine or processed ores, for qualitative or semi-quantitative assessment of the processing performance and, eventually, a trial-and-error optimisation of the operation. But to deliver on its promise, geometallurgy should progress beyond this to provide fully quantitative models of such primary ore characteristics and the performance of their processing, both in average value and, most importantly, keeping track of their uncertainty. Only then it will be possible to optimise the operation in a predictive way. For this goal, we have developed a data mining platform consisting on a SQL database, an R front-end in-house package, and back-ends interpreting data from several analytical instruments into the database. A structured relational SQL database is useful to organise all available information (geometry, phase, chemistry, physical properties) of mineral grains, particles and samples. The R front-end allows to use the statistical and data mining power of this open-source environment in a transparent way for any geomet task, from ore characterisation to process fitting and forecasting, from geostatistical prediction to operational optimisation.
With regard to the back-ends, currently we import XRD, XRF and mineral liberation analysis measurements, and we will incorporate other data sources. The scripting abilities of R allow to process many streams in loop freeing the user of repeating tedious click-and-drop tasks; compute virtually any quantity; distribute the work among several clusters; or keep a log file of the calculations done, for accountability. This contribution presents the building blocks of this package, and their use with several examples in geometallurgical tasks.
Contribution to proceedings
IMPC 2020, 18.-22.10.2020, Cape Town, South Africa
A THz View on Magnetization Dynamics: Opportunities at the THz User Facility TELBE
The control of magnetic order by intense THz radiation is an emerging area in today’s ultra-fast Science community. Many different studies have investigated the interaction between THz fields and magnetic order on sub-picosecond timescales and have demonstrated different mechanisms for THz control. In this contribution, we discuss the opportunities to control the magnetic order of the material using spectrally dense, high repetition rate, narrow band THz pulses at TELBE.
GRC Spin dynamics in nanostructures, 07.07.2019, Les delbrates, Switzerland
All-optical structuring of laser-driven proton beam profiles
Metzkes-Ng, J.; Bernert, C.; Brack, F.-E.; Branco, J.; Bussmann, M.; Cowan, T.; Curry, C. B.; Gaus, L.; Fiuza, F.; Garten, M.; Gauthier, M.; Glenzer, S. H.; Göde, S.; Hübl, A.; Irman, A.; Kim, J. B.; Kluge, T.; Kraft, S.; Kroll, F.; Macdonald, M. J.; Mishra, R.; Obst-Hübl, L.; Pausch, R.; Prencipe, I.; Rehwald, M.; Rödel, C.; Ruyer, C.; Schlenvoigt, H.-P.; Sommer, P.; Schoenwalder, C.; Schumaker, W.; Ziegler, T.; Schramm, U.; Zeil, K.
Extreme field gradients intrinsic to relativistic laser-interactions with thin solid targets enable compact multi-MeV proton accelerators. The initial µm-scale acceleration phase is followed by ballistic proton propagation with negligible space-charge effects over millimeters to hundreds of centimeters to a site of analysis/application. The detected proton distribution can be influenced by the spatio-temporal intensity distribution in the laser focus, electron transport, plasma instabilities, as well as target geometry and surface properties.
Substantially extending this picture, our recent results show a critical influence of the mm-scale vacuum environment on the accelerated proton bunch, where residual gas molecules are ionized by the remnant laser light not absorbed into the target plasma but reflected or transmitted. In an experiment with µm-sized hydrogen jet targets, this effect lead to the counter-intuitive observation of laser near-field feature imprints in the detected proton beam profiles. Our results show that the remnant laser pulse induces a quasi-static deflecting field in the ionized residual background gas that serves as a memorizing medium and allows for asynchronous information transfer to the naturally delayed proton bunch. Occurring under typical experimental laser, target and vacuum conditions, all-optical imprinting needs to be taken into account for sensible interpretation of modulated proton beam profiles.
Keywords: laser-driven ion acceleration
Invited lecture (Conferences)
European Advanced Accelerator Concepts Workshop (EAAC 2019), 15.-21.09.2019, La Biodola, Isola d'Elba, Italien
A THz View on Magnetization Dynamics: Opportunities at the THz User Facility TELBE
The control of magnetic order by intense THz radiation is an emerging area in today’s ultra-fast Science community. Many different studies have investigated the interaction between THz fields and magnetic order on sub-picosecond timescales and have demonstrated different mechanisms for THz control. In this contribution, we discuss the opportunities to control the magnetic order of the material using spectrally dense, high repetition rate, narrow band THz pulses at TELBE. The THz facility at ELBE (TELBE) is one of only a few superradiant THz light sources operated at an SRF accelerator and the only facility worldwide that provides: high THz fields at quasi-CW repetition rates. TELBE is operated in early-stage user operation since 08/2016.
IRMMW 2019, 01.-06.09.2019, Paris, France
Narrow band tunable spintronic THz emission from ferrimagnetic nano-films
We report on narrow band THz emission from ferrimagnetic Mn3-xGa nano-films based. The emission originates from coherently excited spin precession. The central frequency of the emitted radiation is determined by the anisotropy field, while the bandwidth relates to Gilbert damping. It is shown how THz emission can be used for the characterization dynamical properties of ultra-thin magnetic films. We furthermore discuss the potential of these types of films as efficient on-chip spintronic THz emitter.
Keywords: Spintronics, THz emitter, nano-films.
Invited lecture (Conferences)
International Conference on Optics and Electro-Optics 2019, 19.-22.10.2019, Dehradun, India
Active Modes and Dynamical Balances in MRI Turbulence of Keplerian Disks with a Net Vertical Magnetic Field
We studied dynamical balances in magnetorotational instability (MRI) turbulence with a net vertical field in the shearing box model of disks. Analyzing the turbulence dynamics in Fourier (k-)space, we identified three types of active modes that define the turbulence characteristics. These modes have lengths similar to the box size, i.e., lie in the small wavenumber region in Fourier space labeled "the vital area" and are (i) the channel mode, uniform in the disk plane with the smallest vertical wavenumber; (ii) the zonal flow mode, azimuthally and vertically uniform with the smallest radial wavenumber; and (iii) the rest (parasitic) modes. The rest modes comprise those harmonics in the vital area whose energies reach more than 50% of the maximum spectral energy. The rest modes individually are not so significant compared to the channel and zonal flow modes; however, the combined action of their multitude is dominant over these two modes. These three mode types are governed by the interplay of the linear and nonlinear processes, leading to their interdependent dynamics. The linear processes consist of disk flow nonmodality modified classical MRI with a net vertical field. The main nonlinear process is the transfer of modes over wavevector angles in Fourier space—the transverse cascade. The channel mode exhibits episodic bursts supplied by linear MRI growth, while the nonlinear processes mostly oppose this, draining the channel energy and redistributing it to the rest modes. As for the zonal flow, it does not have a linear source and is fed by nonlinear interactions of the rest modes.
Keywords: accretion,; dynamo; instabilities; magnetohydrodynamics (MHD); turbulence; accretion disks
Astrophysical Journal 866(2018), 134
Ionenstrahlen erzeugen periodische, magnetische Domänenstrukturen
Nord, M.; Mcgrouther, D.; Potzger, K.; Bali, R.
Bei der Ausbildung magnetischer Domänen in Nanostrukturen spielt die magnetische Anisotropie eine wesentliche Rolle. Sie kann durch die äußere Form der magnetischen Struktur, aber auch durch Verzerrungen im Kristallgitter beeinflusst werden. In einem Material, dessen magnetische Eigenschaften durch Ionenbestrahlung verändert werden, lassen sich beide Beiträge gleichzeitig erzeugen. Dieses Phänomen hat unsere Gruppe am Helmholtz-Zentrum Dresden-Rossendorf ausgenutzt, um Domänenstrukturen gezielt einzustellen.
Keywords: Magnetismus; Ionenbestrahlung; FeAl
- Physik in unserer Zeit 51(2020)2, 58-59
Ultrasmall silicon nanoparticles as promising platform for multimodal imaging
Ultrasmall renal clearable nanoparticles possess enormous potential as cancer imaging agents [1, 2]. In this perspective, biocompatible silicon nanoparticles (Si NPs) are highly attractive. Their facile surface functionalization allows the introduction of different labels for in vivo imaging. Recently, we have reported on biodistribution of ultrasmall silicon particles (size ~ 4 nm) in small animals by in vivo positron emission tomography (PET) to provide reliable information about absorption, distribution, metabolism, and excretion (ADME) .
Subsequent functionalization of Si NPs with a near-infrared dye (IR800-CW) and a radiolabel (64Cu) enabled a detailed in vitro and in vivo study of the particles of these dual labeled particles. Both PET and fluorescence imaging studies showed a rapid renal clearance from small animals. It has been proven that ultrasmall Si NPs with a surface charge close to zero show fast distribution kinetics and rapid renal clearance. Despite the very small size, multiple and different functionalities can be grafted on the nanoparticle surface. In this way, the pharmacokinetic properties can be tailored and the behavior can be studied in vitro and in vivo in detail.
 Zarschler et al. Nanomedicine: Nanotechnology, Biology, and Medicine. 2016, 12: 1663-1701.
 Kunz-Schughart et al. Biomaterials 2017, 120: 155-184.
Faraday Discussion: Luminescent silicon nanostructures, 12.-14.02.2020, York, UK
Multifunctional Stealth Nanoparticles for Biomedical Applications
Due to their size and surface charge, nanoparticles are often recognised as foreign objects by the body's own immune system and eliminated by its scavenger cells. A special role is played by the opsonisation of the particles, i.e. the surface is coated with special proteins (protein corona) in order to be more easily recognised and absorbed by phagocytic cells. Basically, there are two strategies to avoid phagocytosis. Firstly, the formation of a protein corona on nanoparticles is dramatically reduced by ultrasmall particles (< 5 nm) [1-2] and secondly, there is the possibility of producing so-called "stealth" particles that are invisible to the immune system. Here, the application of a zwitterionic protective coating (see Figure) is frequently used, which minimizes or prevents the surface binding of proteins [3-7].
This lecture will focus on the development and characterization of tiny nanoparticles, embracing silicon quantum dots, superparamagnetic iron oxide and upconverting nanophosphors for biomedical applications.
 L. Boselli, E. Polo, V. Castagnola, K. A. Dawson, Angew. Chem. Int. Ed. 56 (2017) 4215-4218.
 N. Liccardello, S. Hunoldt, R. Bergmann, G. Singh, C. Mamat, A. Faramus, J. L. Z. Ddungu, S. Silvestrini, M, Maggini, L. De Cola, H. Stephan, Nanoscale 10 (2018) 9880-9891.
 K. Pombo-García, K. Zarschler, L. Barbaro, J. A. Barreto, W. O’ Malley, L. Spiccia, H. Stephan, B. Graham, Small 10 (2014) 2516-2529.
 K. Pombo-García, S. Weiss, K. Zarschler, C.-S. Ang, R. Hübner, J. Pufe, S. Meister, J. Seidel, J. Pietzsch, L. Spiccia, H. Stephan, B.Graham, ChemNanoMat 2 (2016) 959-971.
 K. Pombo-García, C. L. Rühl, R. Lam, J. A. Barreto, C.-S. Ang, P. J. Scammels, P. Comba, L. Spiccia, B. Graham, T. Joshi, H. Stephan, ChemPlusChem 82 (2017) 638-646.
 A. Nsubuga, M. Sgarzi, K. Zarschler, M. Kubeil, R. Hübner, R. Steudtner, B. Graham, T. Joshi, H. Stephan, Dalton Trans. 47 (2018) 8595-8604.
 A. Nsubuga, K. Zarschler, M. Sgarzi, B. Graham, H. Stephan, T. Joshi, Angew. Chem. Int. Ed. 57 (2018) 16036-16040.
Invited lecture (Conferences)
3nd International Conference on Translational Chemistry, 02.-05.12.2019, Lissabon-Caparica, Portugal
Applications of ASL in glioma imaging
Invited lecture (Conferences)
Glioma MR imaging 2.0 Action meeting, 12.-13.12.2019, Malta, Malta
Test: Conference presentation
Import text for the presentation.
Keywords: presentation; test
Testkonferenz, 16.-17.12.2019, Dresden, Deutschland
Published in the HZDR-Repository RODARE (Test)
A theranostic drug for prostate cancer CAR T cell immunotherapy and PET imaging
Although chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic efficacy, current design of clinically approved CAR constructs renders therapies monospecific, inflexible and imperiled to severe side effects. We therefore refined the CAR approach and established a switchable platform technology termed UniCAR. Instead of directly interacting with tumor cells, UniCAR‐engrafted T cells recognize the short peptide epitope E5B9. Their on/off switch is mediated by E5B9‐comprising targeting modules (TMs), facilitating indirect cross‐linkage to antigen‐expressing cancer cells.
As all TMs described to date contain an antibody‐derived binding moiety, we aimed to develop a ligand‐based low‐molecular weight agent that enables not only UniCAR T cell retargeting, but also monitoring of the therapeutic response by non‐invasive PET imaging.
For proof of concept of this novel theranostic approach, we successfully converted the clinically approved radiotracer PSMA‐11 into a TM by fusion with E5B9 without affecting its diagnostic properties in mice and humans. Moreover, the chemically synthesized, ligand‐based compound efficiently mediated PSMA‐expressing tumor cell lysis by UniCAR T cells both in vitro and in vivo.
Taken together, the PSMA‐ligand TM represents a novel theranostic agent that is an attractive candidate for immunotherapy of prostate cancer as well as for initial diagnosis and follow‐up treatment.
Abstract in refereed journal
Human Gene Therapy 30(2019)12, ICLEa19‐0024
International Conference on Lymphocyte Engineering (ICLE 2019), 13.-15.09.2019, London, United Kingdom
Redirection of UniCAR T cell against EGFR+ tumor cells by using different αEGFR targeting module formats
Since epithelial growth factor receptor (EGFR) mutations or overexpression is linked with variety of malignancies, including lung, breast, stomach, colorectal, head and neck carcinomas as well as glioblastomas, it is an attractive target for tailored treatment. As chimeric antigen receptor (CAR) engineered T cells highly effectively eliminate hematological malignancies already in the clinics, one idea is to redirect CAR T cells also against EGFR expressing solid cancers. However, CAR T cell therapy can lead to severe, even life‐threatening side effects with high risk of on‐target/off‐tumor activity. To overcome these challenges our UniCAR technology might be an appropriate answer combining high anti‐tumor effectiveness, tumor specificity, flexibility, and safety control mechanisms. In contrast to conventional CARs, UniCAR T cells are per se inert because UniCARs are directed against a small peptide epitope, which is not present on living cells. The redirection of UniCAR T cells toward target cells occurs only in the presence of a tumor specific targeting molecule (TM) – bifunctional moieties carrying the specificity for a certain tumor antigen and contain the UniCAR peptide epitope recognized by UniCARs. TMs can be made of different molecules showing various structures. Here we are presenting the comparison in functionality, in vitro and in vivo, of two TM formats: nanobody based αEGFR TM derived from the camelid αEGFR antibody 7C12 and scFv derived TM from the clinically used chimeric monoclonal antibody Cetuximab (IMC C‐225). In principle, we observed that both TM formats are able to redirect UniCAR T cells to eliminate EGFR‐expressing tumor cells in an antigen‐specific and TM‐dependent manner. Most interestingly, the tumor killing efficiency of the αEGFR scFv TM was significantly superior in comparison to the nanobody based TM, what might decide whether UniCAR T cells attack target cells showing different EGFR density level.
Abstract in refereed journal
Human Gene Therapy 30(2019)12, ICLEa19‐0036
International Conference on Lymphocyte Engineering (ICLE 2019), 13.-15.09.2019, London, United Kingdom
UniCAR T-cells retargeted via short-lived and extended half-life target modules - a combined approach for cancer immunotherapy
Chimeric antigen receptors (CARs) are highly efficient tools for T‐cell‐based cancer immunotherapy. Nonetheless, this approach is associated with mild to severe toxicities including cytokine release syndrome and on‐target/off‐tumor effects. To increase clinical safety while maintaining the efficacy of CAR T‐cell therapy, we developed a novel modular universal CAR (UniCAR) platform. UniCAR T‐cells are exclusively activated via a target module (TM) that establishes the cross‐link between UniCAR T‐cells and cancer cells. Given the small size of such molecules, they are rapidly eliminated and thus, have to be administrated via continuous infusion. Consequently, activation and possible side effects of UniCAR T‐cells can be easily controlled by TM dosing. Regulation of CAR T‐cell activity is mainly important during onset of therapy when tumor burden and the risk for severe side effects are high. Therefore, TMs with extended half‐life may improve eradication of residual tumor cells in late phase of treatment and further expedite clinical application. In this line of thought, we developed both short‐lived and longer lasting TMs directed against several tumor‐associated antigens. Short‐lived TMs are composed of a tumor‐specific binding moiety and the E5B9 peptide epitope which is recognized by UniCAR T‐cells. In order to generate extended half‐life TMs, these two components are fused to the human IgG4 Fc domain. Both short‐lived and longer lasting TMs efficiently redirect UniCAR T‐cells to cancer cells in a highly target‐specific manner, thereby promoting the secretion of pro‐inflammatory cytokines and tumor cell lysis in vitro and in vivo. As demonstrated by PET‐imaging, all TMs specifically enriched at the tumor site presenting either short or prolonged serum half‐lives. Taken together, combination of different short‐lived and extended half‐life TMs provides a highly promising and customized tool for retargeting of UniCAR T‐cells in a flexible, individualized and safe manner at different phases of tumor therapy.
Abstract in refereed journal
Human Gene Therapy (2019)
International Conference on Lymphocyte Engineering (ICLE 2019), 13.-15.09.2019, London, United Kingdom
- Secondary publication expected
Combinatorial tumor targeting using a novel switchable RevCAR system
Although T-cells genetically modified to express chimeric antigen receptors (CARs) are successfully used to treat hematological malignancies, patients still suffer from several drawbacks of conventional CAR (cCAR) therapy. CAR-T-cells can cause severe to life-threatening adverse reactions like on-target, off-tumor toxicities which cannot be controlled in patients. Moreover, cCAR therapy often fails to successfully affect solid tumors and bears the risk to encourage tumor escape variants upon targeting of only one single tumor-associated antigen (TAA). In order to overcome these problems, we have established a novel on/off-switchable RevCAR system facilitating combinatorial targeting strategies.
For combinatorial targeting one T-cell has to be modified with two separate CARs recognizing different TAAs. The first CAR mediates the activation and the second CAR the costimulatory signal. In case of ‘AND’ gate targeting, dual-CAR-T-cells have to recognize both TAAs on the surface of the target cells to get activated. However, such combinatorial targeting strategies are struggling with several challenges including the adjustment of signal strength and affinity of both split CARs as well as the CAR size limiting the number of transduced specificities. In order to overcome these obstacles, our idea was to construct small RevCARs comprising only a small peptide epitope as extracellular domain. By removing the extracellular single-chain variable fragment (scFv) of cCARs, RevCARs avoid tonic signaling induced by scFv dimerization. As RevCARs do not have an extracellular antigen binding moiety, they cannot bind to any antigen per se. Thus, actually they are switched off. Only in the presence of a bispecific target module (RevTM), RevCAR-T-cells can be redirected to tumor cells and switched on. Finally, short-living RevTMs allow a repeatedly on/off-switch and controllability of RevCAR-T-cells and furthermore a flexible redirection of RevCAR-T-cells to any target.
For proof of concept two small peptide epitopes were selected to construct the respective RevCARs. Additionally, a series of different RevTMs was generated recognizing one of the two peptide epitopes and simultaneously any potential TAA. RevTMs were able to efficiently redirect RevCAR-T-cells specifically against different tumor targets. Moreover, we show that combinatorial targeting can be achieved using our RevCAR system. Here, dual-RevCAR-T-cells were efficiently activated only after engagement by two RevTMs targeting the activating or costimulatory RevCAR and different TAAs.
Taken together, we developed a switchable RevCAR platform showing high effectiveness, increased specificity, improved safety, easy controllability, and small size facilitating combinatorial tumor targeting.
Abstract in refereed journal
Journal for ImmunoTherapy of Cancer 7(2019)Suppl. 1, P174
34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2019), 06.-10.11.2019, National Harbor, Maryland, USA
40Ar/39Ar Geochronology of ICDP PALEOVAN Drilling Cores
The scientific drilling campaign PALEOVAN was conducted in the summer of 2010 and was part of the international continental drilling programme (ICDP). The main goal of the campaign was the recovery of a sensitive climate archive in the East of Anatolia. Lacustrine deposits underneath the lake floor of ‘Lake Van’ constitute this archive. The drilled core material was recovered from two locations: the Ahlat Ridge and the Northern Basin. A composite core was constructed from cored material of seven parallel boreholes at the Ahlat Ridge and covers an almost complete lacustrine history of Lake Van. The composite record offered sensitive climate proxies such as variations of total organic carbon, K/Ca ratios, or a relative abundance of arboreal pollen. These proxies revealed patterns that are similar to climate proxy variations from Greenland ice cores. Climate variations in Greenland ice cores have been dated by modelling the timing of orbital forces to affect the climate. Volatiles from melted ice aliquots are often taken as high-resolution proxies and provide a base for fitting the according temporal models. Colleagues from the PALEOVAN scientific team fitted proxy data from Lake Van to the ice core data and constructed an age model that based on the fitting. Embedded volcaniclastic layers had to be dated radiometrically in order to provide independent age constraints to this climate-stratigraphic age model. Solving this task by an application of the 40Ar/39Ar method was the main objective of this thesis. Earlier efforts to apply the 40Ar/39Ar dating resulted in inaccuracies that could not be explained satisfactorily. Two stratovolcanos are located at the western and the northern shore of Lake Van: Nemrut and Süphan. Both volcanoes have deposited volcaniclastic materials into the lake’s basin throughout the entire lacustrine history of Lake Van. Feldspars and volcanic glasses from rhyolitic and trachytic tephra were analysed for their chemical composition in order to evaluate their suitability as target materials for the 40Ar/39Ar method. The absence of K-rich feldspars in suitable tephra layers implied that crystals needed to be 500 micrometer in size minimum, in order to apply single-crystal 40Ar/39Ar dating. Some of the samples did not contain any of these grain sizes or only very few crystals of that size. In order to overcome this problem this study applied a combined single-crystal and multi-crystal approach with different crystal fractions from the same sample. The preferred method of a stepwise heating analysis of an aliqoute of feldspar crystals has been applied to three samples. The Na-rich crystals and their young geological age required 20 mg of inclusion-free, non-corroded feldspars. Small sample volumes (usually 25 % aliquots of 5 cm3 of sample material – a spoon full of tephra) and the widespread presence of melt-inclusion led to the application of combined single- and multigrain total fusion analyses. 40Ar/39Ar analyses on single crystals have the advantage of being able to monitor the presence of excess 40Ar and detrital or xenocrystic contamination in the samples. Multigrain analyses may hide the effects from these obstacles. The results from the multigrain analyses are therefore discussed with respect to the findings from the respective cogenetic single crystal ages. Some of the samples in this study were dated by 40Ar/39Ar on feldspars on multigrain separates and (if available) in combination with only a few single crystals. 40Ar/39Ar ages from two of the samples deviated statistically from the age model. All other samples resulted in identical ages. The deviations displayed older ages than those obtained from the age model. t-Tests compared radiometric ages with available age control points from various proxies and from the relative paleointensity of the earth magnetic field within a stratigraphic range of 10 m. Concordant age control points from different relative chronometers indicated that deviations are a result of erroneous 40Ar/39Ar ages. The thesis argues two potential reasons for these ages: (1) the irregular appearance of 40Ar from rare melt- and fluid- inclusions and (2) the contamination of the samples with older crystals due to a rapid combination of assimilation and ejection. The contamination with older crystals by detrital processes cannot be excluded due to the analysis of multigrain fractions. However, this process appears unlikely because apparent ages are normally distributed. Another aliquot of feldspar crystals that underwent separation for the application of 40Ar/39Ar dating was investigated for geochemical inhomogeneities. Magmatic zoning is ubiquitous in the volcaniclastic feldspar crystals. Four different types of magmatic zoning were detected. The zoning types are compositional zoning (C-type zoning), pseudo-oscillatory zoning of trace element concentrations (PO-type zoning), chaotic and patchy zoning of major and trace element concentrations (R-type zoning) and concentric zoning of trace elements (CC-type zoning). Samples that deviated in 40Ar/39Ar ages showed C-type zoning, R-type zoning or a mix of different types of zoning (C-type and PO-type). Feldspars showing PO-type zoning typically represent the smallest grain size fractions in the samples. The constant major element compositions of these crystals are interpreted to represent the latest stages in the compositional evolution of feldspars in a peralkaline melt. PO-type crystals contain less melt- inclusions than other zoning types and are rarely corroded. This thesis concludes that feldspars that show PO-type zoning are most promising chronometers for the 40Ar/39Ar method, if samples provide mixed zoning types of Quarternary anorthoclase feldspars. Five samples were dated by applying the 40Ar/39Ar method to volcanic glass. High fractions of atmospheric Ar (typically > 98%) significantly hampered the precision of the 40Ar/39Ar ages and resulted in rough age estimates that widely overlap the age model. Ar isotopes indicated that the glasses bore a chorine-rich Ar-end member. The chlorine-derived 38Ar indicated chlorine-rich fluid-inclusions or the hydration of the volcanic glass shards. This indication strengthened the evidence that irregularly distributed melt-inclusions and thus irregular distributed excess 40Ar influenced the problematic feldspar 40Ar/39Ar ages. Whether a connection between a corrected initial 40Ar/36Ar ratio from glasses to the 40Ar/36Ar ratios from pore waters exists remains unclear. This thesis offers another age model, which is similarly based on the interpolation of the temporal tie points from geophysical and climate-stratigraphic data. The model used a PCHIPinterpolation (piecewise cubic hermite interpolating polynomial) whereas the older age model used a spline-interpolation. Samples that match in ages from 40Ar/39Ar dating of feldspars with the earlier published age model were additionally assigned with an age from the PCHIPinterpolation. These modelled ages allowed a recalculation of the Alder Creek sanidine mineral standard. The climate-stratigraphic calibration of an 40Ar/39Ar mineral standard proved that the age versus depth interpolations from PAELOVAN drilling cores were accurate, and that the applied chronometers recorded the temporal evolution of Lake Van synchronously. Petrochemical discrimination of the sampled volcaniclastic material is also given in this thesis. 41 from 57 sampled volcaniclastic layers indicate Nemrut as their provenance. Criteria that served for the provenance assignment are provided and reviewed critically. Detailed correlations of selected PALEOVAN volcaniclastics to onshore samples that were described in detail by earlier studies are also discussed. The sampled volcaniclastics dominantly have a thickness of < 40 cm and have been ejected by small to medium sized eruptions. Onshore deposits from these types of eruptions are potentially eroded due to predominant strong winds on Nemrut and Süphan slopes. An exact correlation with the data presented here is therefore equivocal or not possible at all. Deviating feldspar 40Ar/39Ar ages can possibly also be explained by inherited 40Ar from feldspar xenocrysts contaminating the samples. In order to test this hypothesis diffusion couples of Ba were investigated in compositionally zoned feldspar crystals. The diffusive behaviour of Ba in feldspar is known, and gradients in the changing concentrations allowed for the calculation of the duration of the crystal’s magmatic development since the formation of the zoning interface. Durations were compared with degassing scenarios that model the Ar loss during assimilation and subsequent ejection of the xenocrystals. Diffusive equilibration of the contrasting Ba concentrations is assumed to generate maximum durations as the gradient could have been developed in several growth and heating stages. The modelling does not show any indication of an involvement of inherited 40Ar in any of the deviating samples. However, the analytical set-up represents the lower limit of the required spatial resolution. Therefore, it cannot be excluded that the degassing modelling relies on a significant overestimation of the maximum duration of the magmatic history. Nevertheless, the modelling of xenocrystal degassing evidences that the irregular incorporation of excess 40Ar by melt- and fluid inclusions represents the most critical problem that needs to be overcome in dating volcaniclastic feldspars from the PALEOVAN drill cores.
This thesis provides the complete background in generating and presenting 40Ar/39Ar ages that are compared to age data from a climate-stratigraphic model. Deviations are identified statistically and then discussed in order to find explanations from the age model and/or from 40Ar/39Ar geochronology. Most of the PALEOVAN stratigraphy provides several chronometers that have been proven for their synchronicity. Lacustrine deposits from Lake Van represent a key archive for reconstructing climate evolution in the eastern Mediterranean and in the Near East. The PALEOVAN record offers a climate-stratigraphic age model with a remarkable accuracy and resolution.
Keywords: Ar/Ar Geochronology; Volcaniclastics; Lake Van; ICDP PALEOVAN; Age Model; Drill Cores; Feldspar; Volcanic Glass
Universität Potsdam, 2019
Mentor: Roland Oberhänsli
Short-lived and extended half-life target modules for redirecting UniCAR T-cells against sialyl-Tn expressing cancer cells
The development of chimeric antigen receptors (CARs) has rapidly emerged as a promising approach in cancer immunotherapy. Nonetheless, drawbacks associated with CAR T cell therapies include on-target/off-tumor effects and cytokine release syndrome. Aiming an increased clinical safety while preserving the efficacy of such therapy, we developed a novel modular universal CAR platform termed UniCAR. UniCAR T-cells are exclusively activated in the presence of a target module (TM), which establishes the cross-link between antigen-specific cancer cells and UniCAR T-cells in an individualized time- and target-dependent manner. The carbohydrate antigen sialyl-Tn (STn) is a particularly interesting target due to its expression in several types of cancer and absence in normal healthy tissues. Given the small size of such TMs, they are rapidly eliminated and thus, possible side effects and activation of UniCAR T-cells can be easily controlled by TM dosing. In late phases of treatment, TMs with extended half-life may play an important role by improving the eradication of residual tumor cells.
In this work, a novel longer-lasting TM against STn was developed, characterized and compared to the previously developed short-lived anti-STn TM. Short-lived TMs are composed of a tumor-specific binding moiety fused to the La peptide epitope (E5B9) which is recognized by UniCAR T-cells. In extended half-life TMs, these two components are fused via an Fc domain derived from the human IgG4 molecule. Functional and pharmacokinetic properties were assessed using in vitro and in vivo assays.
The developed anti-STn IgG4-based TM efficiently activates and redirects UniCAR T-cells to STn-expressing tumors in a highly efficient target-specific and target-dependent manner, promoting the secretion of pro-inflammatory cytokines, tumor cell lysis of breast and bladder cancer cells in vitro and of breast cancer cells in experimental mice. A comparable or increased killing efficiency was obtained at a lower concentration range in comparison to the results obtained for the anti-STn scFv-based TM. Additionally, PET studies demonstrate the specific enrichment of the anti-STn IgG4-based TM at the tumor site presenting a prolonged serum half-life compared to the scFv short-lived TM.
Taken together, these data demonstrate the effective and potential application of this CAR T cell-derived modular system to target STn in different types of cancer using different TM formats. The use and combination of such molecules with different formats and half-lives provides highly promising and customized tools for retargeting of UniCAR T-cells in a flexible, individualized and safe manner at different stages of treatment.
Abstract in refereed journal
Journal for ImmunoTherapy of Cancer 7(2019)
34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2019), 06.-10.11.2019, National Harbor, Maryland, USA
Targeting the FMS-like Tyrosin Kinase 3 with the Unicar System: Preclinical Comparison of Murine and Humanized Single-Chain Variable Fragment-Based Targeting Modules
Clinical translation of chimeric antigen receptor (CAR) T cell therapy in myeloid malignancies is progressing slowly compared to its success in treatment of B cell malignancies. Clinical experiences with CAR T cell therapies against the currently investigated tumor-associated antigens (TAA) (e.g. CD33, CD123 and FMS-like tyrosine kinase 3 (FLT3)) were discouraging and severe side effects occurred (cytokine release syndrome, neurotoxicity and myeloid aplasia) (Hoffmann et al. Journal of Clinical Medicine 2019). Probably targeting a single TAA is insufficient to treat high risk myeloid malignancies with CAR T cell therapies. Therefore, combined targeting of two or even more TAAs seems to be a promising approach. In order to implement such a multiple tumor targeting strategy, we developed a modular CAR T cell system termed UniCAR. The system consists of a universal CAR (UniCAR) directed against the La peptide epitope E5B9 combined with single-chain variable fragment (scFv) -based target modules (TM). In contrast to conventional CARs, anti-tumor activity of UniCAR T cells is only turned on in the presence of the TMs. Thus, this approach will allow UniCAR T cell control due to the short half-life of the TM and therefore has a favorable safety profile. Furthermore, different TMs against several TAAs can be administered both sequentially or in parallel to increase the anti-tumor efficacy or face disease relapse due to antigen escape mechanisms. In the field of myeloid malignancies our group developed retargeting strategies against the TAAs CD33 and CD123 (Cartellieri et al. Blood Cancer Journal 2016). In addition, we have developed a new TM for the UniCAR system that is directed against the TAA FLT3. FLT3 is highly expressed on acute myeloid leukemia (AML) cells and also present on CD123low AML samples (Riccioni et al. British Journal of Haematology 2011).
The novel FLT3 TM was constructed by fusion of the variable domain of the heavy and the light chain of the murine anti-FLT3 monoclonal antibody (4G8) to the E5B9 UniCAR epitope. In light of a potential clinical application, we in parallel generated a humanized FLT3 TM to further decrease its immunogenicity. Both FLT3 TMs were tested in vitro against different AML cell lines, by using flow cytometry based killing assays as described elsewhere (Fasslrinner et al. British Journal of Haematology 2019). The functionality of the FLT3 TMs in vitro was highly effective. Both FLT3 TMs were able to redirect UniCAR T cells for AML cell lysis already in the picomolar range and were moreover comparable effective than the previously developed CD123 TM. Thus, humanization of the FLT3 TM did not lead to a decrease in anti-tumor efficacy.
In summary, we could show that both the novel murine FLT3 TM and the humanized counterpart redirected UniCAR T cells and induced highly effective elimination of AML cells in vitro. Thus, the flexible application of the FLT3-based UniCAR system seems to be a promising tool for cell-based AML therapy alone or even in combination with other AML-specific TMs (e.g. CD33, CD123).
Abstract in refereed journal
BLOOD 134(2019), 5614-5614
- Secondary publication expected
A Novel Revcar Platform for Switchable and Gated Tumor Targeting
Hematological malignancies are successfully treated with chimeric antigen receptor (CAR) armed T cells. Despite the clinical success, CAR T cell therapy struggles still with some problems including the selection of tumor escape variants and on-target, off-tumor side reactions as well as massive cytokine release and uncontrollability of CAR T cell activity in the patients. In order to enable controllability of CAR T cells and to avoid unspecific side effects, we established a novel switchable, split and adaptable CAR platform technology, termed RevCAR system.
The novel RevCARs lack the single chain variable fragment (scFv) commonly used as extracellular domain in conventional CARs. Instead of the scFv, RevCARs contain only a small peptide epitope as extracellular portion. This design reduces the CAR size, avoids unspecific antigen binding and prevents antigen independent tonic signaling caused by scFv dimerization. As RevCAR T cells do not recognize anything, they are per se inert. Only in the presence of a corresponding bispecific antibody based target module (RevTM) they can be specifically redirected to tumor cells. Therefor RevTMs consist of two scFvs. One recognizes the RevCAR peptide epitope and the other one simultaneously binds to a tumor associated antigen (TAA). By dosing of the RevTM, which has a very short half-life, the reactivity of RevCAR T cells can be switched on and off reversibly. Another advantage is that the RevCAR system can be flexibly adapted to any tumor antigen simply by exchanging the RevTM. Furthermore, the small RevCAR size is favorable for inserting more than one RevCAR in the same T cell thus facilitating the mode of gated targeting which is a highly attractive approach to minimize the risk for on-target, off-tumor toxicities against healthy tissues and to increase tumor specificity of conventional CAR T cells. For 'AND' gate targeting via the RevCAR system, two different RevCARs were constructed and expressed simultaneously in the same T cell. The two RevCARs differed with respect to the extracellular peptide epitope and the intracellular signaling domain. Moreover, the respective transmembrane domain was selected to isolate the respective RevCAR signal. The first RevCAR is designed to transmit the activation signal, the second RevCAR to deliver a costimulatory signal. For efficient RevCAR T cell activation, both RevCARs must be engaged via their respective RevTM which on the one hand binds to one of the two RevCAR epitopes and on the other hand to one of two TAAs expressed on the same target cell. Here, we present two RevCAR/RevTM systems for retargeting of AML cells as well as solid tumor cells including via gated targeting.
In summary, we show proof of concept for a novel switchable RevCAR system that can be used for retargeting of AML cells as well as solid tumors. The novel modular RevCAR platform is characterized by small size, lacks unwanted tonic signaling effects, allows the control of RevCAR T cell activity, enables gated targeting strategies, and can be adapted to any tumor antigen and tumor type.
Abstract in refereed journal
BLOOD 134(2019), 5611-5611
- Secondary publication expected
TU Bergakademie Freiberg beteiligt sich an der Fachkräfteinitiative GlasCampus Torgau
In Zusammenarbeit mit dem Landkreis Nordsachsen, dem Beruflichen Schulzentrum Torgau sowie Unternehmen und Verbänden beteiligt sich die TU Bergakademie Freiberg am GlasCampus Torgau. Ziel der gemeinsamen Initiative sind die Gewinnung und Qualifizierung von Fachkräften sowie die Förderung des Fachkräftenachwuchses für die mitteldeutsche Glas-, Keramik- und Baustoffwirtschaft. Daneben soll die Innovationskraft der Unternehmen durch die Förderung des Wissens- und Technologietransfers sowie kooperativer Forschungs- und Entwicklungsaktivitäten gestärkt werden.
Keywords: GlasCampus Torgau; Fachkräfte; Wissenstransfer; Technologietransfer
Contribution to external collection
Gerhard Roewer, Peter Seidelmann, Birgit Seidel-Bachmann, Helmuth Albrecht, Ulrich Groß: ACAMONTA Zeitschrift für Freunde und Förderer der TU Bergakademie Freiberg, Freiberg: Freunde und Förderer der TU Bergakademie Freiberg, 2019
Development of Target Modules for Early and Late Stage Cancer Treatment Using Switchable Unicar T Cell Therapy
The clinical efficacy of CAR T cell therapies has been widely recognized, particularly in the treatment of hematologic malignancies. Nevertheless, CAR T cells also have the capability to elicit undesired effects such as on-target/off-tumor recognition and cytokine release syndrome. To increase clinical safety of CAR T cell therapy, a novel modular universal CAR platform termed UniCAR was developed by our group. In the UniCAR system, antigen-binding specificity and signaling features are two distinct moieties, in which the antigen specificity is provided by targeting modules (TMs) to redirect UniCAR T cells in an individualized time- and target-dependent manner. In this way, UniCAR T-cells acquire killing potential only in the presence of a tumour-specific TM. Given the reduced size of such molecules, they are rapidly eliminated and therefore, need to be continuously infused. Thus, possible side effects and activation of UniCAR T cells can be easily monitored and controlled by TM dosing. During the onset of therapy, tumor burden and the risk for severe side effects are high and regulation of CAR T cell activity is particularly important at this stage. For this reason, TMs with extended half-life may play an important role by improving eradication of residual tumor cells in late phases of treatment and further expedite clinical application. In this line of thought, a set of novel short-lived and longer-lasting TMs directed against several tumor-associated antigens was developed. Short-lived TMs are composed of a tumor-specific binding moiety fused to the La peptide epitope (E5B9) which is recognized by UniCAR T cells. In order to generate extended half-life TMs, these two components are fused via an Fc domain derived from the human IgG4 molecule. In vitro and in vivo assays have shown that both short-lived and longer-lasting TMs efficiently redirect UniCAR T cells to cancer cells in a highly target-specific manner, thereby promoting the secretion of pro-inflammatory cytokines and tumor cell lysis. Further assays using PET-imaging, demonstrated that all TM formats specifically enriched at the tumor site presenting either short or prolonged serum half-lives. From a clinical point of view, after the initial reduction of tumor burden promoted by the small TMs, IgG4-based TMs could be subsequently administrated allowing a more convenient and personalized treatment of the patients avoiding the continuous infusion of the short-lived TMs. Furthermore, the specific accumulation of such IgG4-based TMs at the tumor site sets these molecules as attractive candidates for in vivo imaging and endoradiotherapy. Taken together, combination of switchable UniCAR T cells and TMs with different sizes, specificities and half-lives represent a flexible and individualized approach at different stages of cancer treatment.
Abstract in refereed journal
BLOOD 134(2019), 5613-5613
- Secondary publication expected
The use of pure oxygen for aeration in aerobic wastewater treatment: a review of its potential and limitations
In aerobic wastewater treatment, aeration is the most critical element of the treatment system. It supplies microorganisms with the required amount of dissolved oxygen, maintains solids in suspension and controls membrane fouling, where needed. However, conventional activated sludge, where air is used, is limited to low-strength wastewaters as higher loadings or more intense feeds require both higher biomass and dissolved oxygen concentrations. In membrane bioreactors, despite being able to operate at higher biomass concentrations, their operation at high biomass concentrations and high organic loadings has not been tested. By replacing air with pure oxygen, oxygen transfer rates increase at lower flowrates. In this work, the potential and limitations of pure oxygen systems over conventional ones are reviewed. Also, the effect of the operational parameters or the mixed liquor characteristics on oxygen transfer is determined. Pure oxygen affects bacterial structure, controls foam formation, improves bacterial enzymatic activity and, in membrane bioreactors, leads to a better recovery of permeability after cleanings. It treats much higher loadings without compromising final effluent quality. Fine bubbles are more efficient in oxygen transfer due to their increased contact area. Nevertheless, pure oxygen aeration at times is not essential or it may generate effluent organic matter of a higher refractory character. We then recommend that it be used to applications where conventional aeration is not adequate.
Keywords: aerobic treatment; activated sludge; membrane bioreactor; pure oxygen; fine bubbles
Bioresource Technology 312(2020), 123595
- Final Draft PDF 528 kB Secondary publication
Development of Novel Anti-CD10 Target Modules for Redirection of Universal CAR T Cells Against CD10-Positive Malignancies
The common acute lymphoblastic leukemia antigen CD10 is a marker for several hematological malignancies, including acute lymphoblastic leukemia as well as T and B cell lymphomas, Burkitt lymphomas, and some solid tumors like renal cell carcinomas, pancreatic tumors and melanomas. Because of its tumor related expression pattern, CD10 is an attractive target for adoptively transferred T cells that are genetically modified to express chimeric antigen receptors (CARs). Recently, conventional CAR T cell therapy targeting CD19-positive hematological malignancies was clinically approved because of its impressive effectiveness in patients. However, CAR T cells can also cause severe side effects like on-target, off-tumor reactions, tumor lysis syndrome and cytokine release syndrome. Most critically, activity of conventional CAR T cells cannot be controlled, once they are applied in patients. As CD10 is also widely expressed on normal tissues, CAR T cell reactivity has to be controllable in order to stop CAR T cell therapy in case of on-target, off-tumor toxicities occur. Especially for this purpose, we have recently established a switchable, modular and universal CAR platform technology, named UniCAR system, which can be repeatedly turned on and off. In contrast to conventional CARs, that directly recognize a tumor-associated antigen (TAA) on the tumor cell surface via their extracellular single-chain variable fragment (scFv), the UniCAR system is structured in a modular manner of two components. The first component are T cells genetically engineered to express UniCARs and the second component are target modules (TMs). Most importantly, UniCARs cannot directly bind to a TAA because their extracellular scFv is directed against the peptide epitope E5B9 which is not present on the surface of living cells. Consequently, UniCAR armed T cells are per se inert. They can be redirected towards tumor cells only via a TM. TMs consist of a scFv targeting a TAA and the epitope E5B9 recognized by UniCARs allowing a cross-linkage of UniCAR T cells with tumor cells which results in T cell activation. As TMs have a very short half-life, UniCAR T cell activity can be controlled by dosing of the TM. Once the TM is administered, UniCAR T cells can be switched on, but once the TM injection is stopped and the TM is eliminated, UniCAR T cells are switched off immediately. Here, we show proof of concept for functionality of the UniCAR system targeting CD10-positive malignancies. Therefor, a novel anti-CD10 TM was constructed which is able to redirect UniCAR T cells to eliminate CD10-expressing tumor cells. In summary, we have established a universal, switchable, modular UniCAR platform technology that can be used to target CD10-positive malignancies.
Abstract in refereed journal
BLOOD 134(2019), 5612-5612
- Secondary publication expected
Self-assembled surface nanopatterns for magnetic anisotropy engineering
The focus of this presentation will be nanopatterning by different self-assembly mechanisms and how it can be applied for influencing the magnetic properties, mainly magnetic shape anisotropy, of materials.
We would like to show that well-established macroscopic material processing techniques – broad-beam ion irradiation, high-temperature annealing, and physical vapor deposition – can be used to fabricate nanopatterned materials in a bottom-up fashion and to give them tuneable magnetic properties.
IOM Kolloquium, 25.04.2019, Leipzig, Deutschland
Demonstration of a Broadband Photodetector Based on a Two-Dimensional Metal- Organic Framework
Metal-organic frameworks (MOFs) are emerging as an appealing class of highly tailorable electrically-conducting materials with potential applications in opto-electronics. Yet, the realization of their proof-of-concept devices remains a daunting challenge, attributed to their poor electrical properties. Following our recent report on a semiconducting Fe3(THT)2(NH4)3 (THT, 2,3,6,7,10,11-triphenylenehexathiol) two-dimensional MOF with record-high mobility and band-like charge transport, here, we demonstrate Fe3(THT)2(NH4)3 MOF-based photodetector operating in photoconductive mode capable of detecting a broad wavelength excitation of charge carriers. The narrow IR bandgap of the active layer (~0.45 eV) constrains the performance of the photodetector at room temperature by band-to-band thermal. At 77 K, the device performance is significantly improved; two orders of magnitude higher voltage responsivity, lower noise equivalent power, and higher specific detectivity of 7×108 cm Hz1/2 W–1 are achieved under 785 nm excitation. These figures of merit are retained over the analyzed spectral region (400–1575 nm) and are commensurate to those obtained with the first demonstrations of graphene and black phosphorus based photodetectors. This work demonstrates the feasibility of integrating conjugated MOFs as an active element into broadband photodetectors, thus bridging the gap between materials’ synthesis and technological applications.
Keywords: metal-organic frameworks; broadband photodetectors; low-temperature photodetection; two-dimensional semiconductors; photosensitivity
Advanced Materials 32(2020)9, 16644666
Online First (2020) DOI: 10.1002/adma.201907063
Effect of melt stirring during casting on the extrusion and mechanical properties of wrought aluminium alloys
Räbiger, D.; Willers, B.; Eckert, S.
The adjustment of fine grain morphologies has been approved to be a crucial issue for improving characteristics and properties of cast and wrought aluminium alloys. Several methods are known to achieve grain refinement in solidification processes: add-on of grain refiners, rapid cooling conditions, mechanical or electromagnetic stirring or ultrasonic treatment.
AC magnetic fields provide a contactless method to control the flow inside a liquid metal and the grain size of the solidified ingot. Many studies have shown that beneficial effects like a distinct grain refinement or the promotion of a transition from a columnar to an equiaxed dendritic growth (CET) can be obtained. However, electromagnetically-driven melt convection may also produce segregation freckles on the macroscale. The achievement of superior casting structures needs a well-aimed control of melt convection during solidification.
Previous investigations considered the use of time-modulated AC magnetic fields to control the heat and mass transfer at the solidification front. It has been shown recently under laboratory conditions that an accurate tuning of the magnetic field parameters can avoid segregation effects and homogenize the mechanical properties.
This present study examines the directional solidification of commercial wrought aluminium alloys EN AW 6082 from a water-cooled copper chill. Rotating time-modulated magnetic fields were used to agitate the melt. The impact of flow on the resulting macro and micro structure are investigated. The solidified structure was reviewed in comparison to an unaffected solidified ingot and ingot prepared with chemical grain refiner Ti3B. In addition results from extrusion process experiments and the achieved mechanical properties are introduced. Our results demonstrate the potential of time–modulated magnetic fields to control the grain size and to open the possibility to reduce the amount of grain refiner and to reduce the press capacity.
Keywords: wrought aluminium alloys; mechanical properties; electromagnetic stirring; forced convection
LightMAT 2019 - 3rd International Conference on Light Materials – Science and Technology, 05.-07.11.2019, Manchester, United Kingdom
TEM observation of loops decorating dislocations and resulting source hardening of neutron-irradiated Fe-Cr alloys
Several open issues remain concerning the quantitative understanding of irradiation hardening in high-Cr steels. One of these issues is addressed here by correlating yield points that are observed in stress-strain curves with dislocation decoration observed by TEM for neutron-irradiated Fe-Cr alloys. It is found that both higher neutron exposure and higher Cr content promote irradiation-induced loops to arrange preferentially along dislocation lines. Consequently, the activation of dislocation sources requires unlocking from the decorating loops, thus resulting in a yield drop. This process is considered within the source hardening model as opposed to the dispersed barrier hardening model, the latter aimed to describe dislocation slip through a random array of obstacles. Microstructure-informed estimates of the unlocking stress are compared with measured values of the upper yield stress. As functions of neutron exposure, a cross-over from the dominance of dispersed-barrier hardening accompanied by smooth elastic-plastic transitions to the dominance of source hardening accompanied by yield drops is observed for Fe-9% Cr and Fe-12% Cr.
Keywords: iron-chromium alloy; neutron irradiation; hardening; tensile test; dislocation loop; TEM
Metals 10(2020), 147
Electron Population Dynamics in Optically Pumped Asymmetric Coupled Ge/SiGe Quantum Wells: Experiments and Models
Ciano, C.; Virgilio, M.; Bagolini, L.; Baldassarre, L.; Rossetti, A.; Pashkin, O.; Helm, M.; Montanari, M.; Persichetti, L.; Di Gaspare, L.; Capellini, G.; Paul, D. J.; Scalari, G.; Faist, J.; de Seta, M.; Ortolani, M.
n-type doped Ge quantum wells with SiGe barriers represent a promising heterostructure system for the development of radiation emitters in the terahertz range such as electrically pumped quantum cascade lasers and optically pumped quantum fountain lasers. The non-polar lattice of Ge and SiGe provides electron-phonon scattering rates that are one order of magnitude lower than polar GaAs. We have developed a self-consistent numerical energy-balance model based on a rate equation approach which includes inelastic and elastic inter- and intra-subband scattering events and takes into account a realistic 2DEG distribution in all the subband states of the Ge/SiGe quantum wells by considering subband-dependent electronic temperatures and chemical potentials. This full-subband model is here compared to the standard discrete-energy-level model, in which the material parameters are limited to few input values (scattering rates and radiative cross-sections). To provide an experimental case study, we have epitaxially grown samples consisting of two asymmetric coupled quantum wells forming a three-level system, which we optically pump with a free electron laser. The benchmark quantity selected for model testing purposes is the saturation intensity at the 1-3 intersubband transition. The numerical quantum model prediction is in reasonable agreement with the experiments and therefore outperforms the discrete-energy-level analytical model, whose prediction of the saturation intensity is off by a factor 3.
Keywords: quantum wells; intersubband transitions; terahertz quantum cascade laser; electron-phonon interaction; optical pumping; free electron laser; silicon-germanium heterostructures; infrared spectroscopy; intersubband photoluminescence
Photonics 7(2020)1, 2
Liquid Metal Batteries
Weber, N.; Personnettaz, P.; Weier, T.
Liquid metal batteries (LMBs) are fascinating electrochemical cells. Built as a stable density stratification of two liquid metals separated by a molten salt electrolyte, such cells offer cheap stationary energy storage and a long life time. Due to the totally liquid interior of the cells, fluid flow is of paramount importance for the safe operation of LMBs. As highly resistive electrolyte needs to be as thin as possible, a strong fluid flow might easily wipe it away and short circuit the cell. Aside from that, a slight flow might be highly beneficial. When discharing a Li-Bi LMB, Li will cross the electrolyte layer and alloy into Bi. As this process is diffusion-controlled, a Li-rich layer will build up on top of the positive electrode. A mild flow might equalize the alloy, thus reducing concentration polarization and improving the cell's efficiency.
The talk will first explain the set-up and operation of liquid metal batteries. Afterwards, different possible flow mechanisms in LMBs will be presented and discussed. These will include thermally driven Rayleigh-Benard convection, solutal convection, pinch effects, interface instabilities, the Tayler instability and electro-vortex flow. Besides of flow simulation, the modelling of the electric potential distribution, the current density and magnetic fields will be presented. Special attention will be paied to the implementation of the solvers in OpenFOAM, as well as the description of specialized discretisation schemes, which are necessary e.g. for computing the current density. Finally, it will be shown how different flows in the battery effect the cell voltage, and the integrity of the three layers.
15th OpenFOAM Workshop, 23.06.2020, Arlington, USA
Ionisation chamber readings for proton beams in magnetic fields require dose correction factors
Objectives: Proton therapy (PT) reduces the integral dose in healthy tissue compared to X-ray therapy (XT). At the same time PT is more sensitive to anatomical changes and organ motion than XT, making MRI guidance especially relevant for PT. Recently, we have integrated for the first time a 0.22 T in-beam MRI scanner with a proton therapy research beamline. As a next step, absolute and relative dosimetry in the presence of magnetic fields of the MRI scanner has to be established. This work investigates the influence of the static magnetic (B0) field of the MRI scanner on ionisation chamber (IC) readings for proton beams and the feasibility to correct the readings for the B0 field.
Materials & methods: Either a Semiflex 0.3 or a PinPoint3D IC was positioned in an MR-compatible water phantom to measure the absolute dose at five proton energies (70, 110, 150, 190, 226.7 MeV) in the entrance plateau area of the Bragg curve for a 10 x 10 cm2 pencil beam scanned irradiation field. The entrance window of the phantom was placed at the imaging isocentre of the MRI scanner. Dose measurements were repeated at the same position and under the same conditions without the B0 field. The IC signal was corrected to standard environmental conditions and for the beam quality.
Results & Conclusion: Systematic energy-dependent differences between dose readings with and without the B0 field were observed. For the Semiflex 0.3, the measured dose in the presence of the B0 field increased by 0.75%, 0.58%, 0.59% and 0.41% for 70 MeV, 110 MeV, 150 MeV and 190 MeV, respectively, and decreased by 0.36% for 226.7 MeV. For the same energies, the dose measured by the PinPoint3D increased by 0.81%, 0.69%, 0.63%, 0.47% and 0.31%. For all energies, the standard deviations were smaller than 0.10% and 0.19% for the Semiflex 0.3 and PinPoint3D IC, respectively.
Beam energy-dependent correction of IC readings is mandatory and appears feasible for accurate proton beam dosimetry in magnetic fields.
Keywords: dosimetry; MRgPT; correction factor; magnetic field
eDGMP 2020, 09.-11.09.2020, Leipzig, Deutschland
Inverse gas chromatography studies of the esterification of glass particles with different morphologies
The separation of fine particles is a challenging task where a proper understanding of the interfacial properties is crucial. In our research, we focus on flotation, which is a powerful and widely used separation technique, where valuable mineral particles are selectively separated from unwanted gangue, with particles in the size range of about 10 µm to 200 µm. For this process, particle properties such as wettability, size or morphology are fundamental separation features.
Although, it is a well-established processing technique that is used all over the world in industry, there are still some challenges with regard to the processing of ultrafine particles with sizes below 10 µm. The aim of this project, which is part of the German research foundation priority programme DFG-SPP 2045 “MehrDimPart”, is to gain a deeper understanding of the microprocesses that occur during flotation and to have a closer look on the influence of particle properties, like wettability and morphology.
For this research glass particles are used as their surface chemistry can be modified in different ways. Here, the functionalisation was carried out by esterification with alcohols, where the wettability of the product can be controlled by the length of the alkyl chain. In order to investigate the effect of particle morphology on flotation three differently shaped glass particles were used and esterified, including fibres, spheres and fragments with differing shapes. Inverse gas chromatography is used to characterise the particles surface energy distributions, which provide information about the particles wettability as well as the heterogeneity of the surface.
Keywords: Ultrafine Particles; Surface Modification; Esterification of Glass Particles; Hydrophobisation; Surface Energy Distribution; Inverse Gas Chromatography; Flotation
8th International IGC Symposium, 04.06.2019, Köln, Deutschland
The effect of morphology of microparticles hydrophobized via esterification with alcohols on the specific surface energies distributions
Froth flotation is a well-established and efficient particle processing technique especially for the selective separation of mineral particles from unwanted material within sizes ranging from 10 µm to 200 µm. However, there are still some challenges and unexplored opportunities when it comes to the separation of ultrafine particles (< 10 µm). Within the German research foundation priority programme DFG-SPP 2045 “MehrDimPart” we aim to develop a novel multidimensional separation device for such ultrafine particles based on the particle parameters of wettability, morphology (shape or roughness) and size.
One important aspect of our investigations in this new flotation device lies in the modification of the materials surface, which is achieved via esterification with alcohols. To study the effect of the particle morphology/shape on the hydrophobization of glass microparticles, three differently shaped but same sieve sized fractions are used for applying esterification, among them spherical particles, elongated particles and particle fragments with varying shapes. The characterisation of the particle wettability is realised using the inverse gas chromatography method with additional information on the surface energy components distributions. The wettability is varied using alcohols with different chain length and the resulting surface energy components distributions are put in context with flotabilities of the particles in two flotability characterisation set-ups, i.e. tube microflotation and particle adhesion to hydrocarbons.
Keywords: Ultrafine Particles; Surface Modification; Esterification of Silica; Hydrophobisation; Surface Energy Distribution; inverse Gas Chromatography; Flotation
PARTEC 2019 - International Congress on Particle Technology, 09.-11.04.2019, Nürnberg, Deutschland
Solution-Phase Synthesis of the Fluorogenic TGase 2 Acyl Donor Z-Glu(HMC)-Gly-OH and its Use for Inhibitor and Amine Substrate Characterisation
A reliable solution-phase synthesis of the water-soluble dipeptidic fluorogenic transglutaminase substrate Z-Glu(HMC)-Gly-OH is presented. The route started from Z-Glu-OH, which was converted into the corresponding cyclic anhydride. This building block was transformed into the regioisomeric - and -dipeptides. Key step was the esterification of Z-Glu-Gly-OtBu with 4-methylumbelliferone. The final substrate compound was obtained in an acceptable yield and excellent purity without the need of purification by RP-HPLC. The advantage of this acyl donor substrate for the kinetic characterisation of inhibitors and amine-type acyl acceptor substrates is demonstrated by evaluating commercially available or literature-known irreversible inhibitors and the biogenic amines serotonin, histamine and dopamine, respectively.
Keywords: fluorogenic enzyme substrates; side-chain esterified peptides; aryl esters; peptide synthesis; enzyme kinetics; biogenic amines
Analytical Biochemistry 595(2020), 113612
- Final Draft PDF 3 MB Secondary publication
Simulation of coolant mixing in a BWR spent fuel storage pool and flood chamber
The waiting times in case of failure of the cooling system of the spent fuel storage pool were determined with the three-dimensional numerical calculation tool ANSYS CFX. With the calculated variant, it is assumed that the swivel gate is opened when required. For the decay heat of 1.5 MW, waiting times until the spent fuel storage pool has been heated to 60 °C or 80 °C were calculated and the temperature offset between the spent fuel storage pool and the storage chamber pool was determined.
The calculations showed that the coolant from the flood chamber and the storage chamber, which is located above the lower edge of the open swivel gate, mixes ideally with the water from the spent fuel pool. The results of the CFD analysis can be used for the cross-code verification of models in integral codes.
Keywords: Boiling; CFD; Mixing; spent fuel storage pool
Nuclear Engineering and Design 359(2020), 110468
- Secondary publication expected
Helium Ion Microscope Imaging and Time-of-Flight Secondary Ion Mass Spectrometry depth profiling of sample cross sections
The Helium ion microscope is well known for its high-resolution imaging and nanofabrication performance. We have recently developed and presented a time-of-flight based secondary ion mass spectrometer that can be retrofitted to existing microscopes [1, 2].
Depth profiling in SIMS in general is usually done by sputtering into deeper layers and plotting the signal intensity over time. The actual milling depth can only be estimated and the common approach is to measure the crater depth with atomic force microscopy every time a compositional change is observed.
Direct imaging and chemical analysis of a cross-section with high spatial resolution can avoid this challenge. The cross sections will be prepared ex-situ by milling, grinding and low energy argon ion polishing.
 Klingner, N.; Heller, R.; Hlawacek, G.; von Borany, J.; Notte, J. A.; Huang, J. and
Facsko, S.; Ultramicroscopy 162(2016), 91-97
 Klingner, N.; Heller, R.; Hlawacek, G.; Facsko, S. and von Borany, J.; Ultramicroscopy 198(2019), 10-17
PicoFIB - Advances in Gas-Ion Microscopy, 20.01.2020, Sheffield, United Kingdom
Numerical simulation of adiabatic two phase flow in horizontal elbow bends
In industry there is need for predicting the morphology of two-phase liquid-gas flows that are part of e.g. distillation processes, pipeline transport units, chemical reactors or heat transfer units. Knowledge of the behavior of the flow and its regime facilitate for the engineers to have proper design of downstream processes and the pipeline in order to achieve the best reliable and economic outcome. One topic that is not studied sufficiently is the characterization of not fully developed flow due originated from insufficient developing or calming length as it can be found downstream of elbow bends and in short straight pipes, which are frequently encountered in industrial applications. In order to study this topic and characterize the flows, an experimental instrumentation was set up using Wire-mesh Sensors. This work is a numerical work using ANSYS CFX 19.1 in order to set up simulations of the experimentally investigated pipe geometries and flow regimes, followed by validation with the WMS data. Therefore, this work is concerned with gas-liquid flow in a horizontal straight pipe of DN50 and DN200 and horizontal elbow bends with the same diameters and curvature ratio of R/D=1. Each of the geometries is studied for annular and stratified wavy flow.
Grenoble INP, 2019
Mentor: Alexander Döß
Charakterisierung von Zweiphasenströmungen in komplexen Rohrgeometrien
Die vorliegende Arbeit beschäftigt sich mit der Charakterisierung einer Zweiphasenströmung durch eine komplexe Rohrgeometrie in Form eines horizontalen 90°-Rohrbogens mit einem Innendurchmesser D = 50mm und einem relativen Radius R=1 . Basierend auf experi-mentellen Gittersensordaten wird der Bereich stromauf- und stromabwärts der Bogengeometrie untersucht. Die experimentellen Untersuchungen erfolgten an einer horizontalen, nicht vollständig eingelaufenen Zweiphasenströmung. Schwerpunkt der Untersuchungen war da-bei die Beurteilung des Einflusses der Rohrleitungslänge. Ein bleibender Einfluss des Rohrbogens auf die Strömungsmorphologie konnte nicht festgestellt werden. Für die Bestimmung des Gasanteils und des Zweiphasendruckverlustes wurden existierende Modellansätze systematisiert und bezüglich der Anwendung auf nicht eingelaufende Zweiphasenströmungen, bzw. den Bereich des Rohrbogens überprüft. Basierend auf der Abweichung der Korrelationen wurden kombinierte Berechnungsansätze für den Gasanteil und den Zweiphasendruck-verlust ausgewählt, welche die experimentellen Daten mit bester Näherung korrelierten.
TU Dresden, 2019
Mentor: Alexander Döß
Towards the clinical translation of the adenosine A2A receptor (A2AR) radioligand [18F]FLUDA: preclinical perspectives
The A2AR has emerged as a potential therapeutic target due to its involvement in basic functions of the neuronal, cardiovascular and immune systems. Blockade of A2AR is regarded as potential tool related to CAR T-cell immunotherapy of cancer. Furthermore, A2AR are believed to regulate myocardial oxygen demand and to increase coronary circulation by vasodilation. With regard to Parkinson’s disease A2AR antagonists, such as the FDA approved Nourianz®, are used as an adjunctive treatment to levopoda®. Therefore noninvasive imaging to monitor changes of receptor density and/or occupancy during the A2aR-tailored therapy is of utmost importance. We recently developed the A2AR PET radiotracer [18F]FLUDA which demonstrated superior pharmacokinetic properties among the radiotracers available. Towards its clinical translation, an automated radiosynthesis was developed and the radiotracer was fully characterized in vitro and in vivo including toxicity and dosimetry1 studies.
The binding affinity (Ki) of FLUDA towards the human A2AR and A1R subtypes was estimated in vitro by competitive radioligand binding assays. In addition, selectivity studies were performed. An automated two-step one-pot radiosynthesis of [18F]FLUDA was developed. In vitro autoradiography was performed on cryosections of mice brain. Dynamic PET/MR studies under baseline and blocking conditions were assessed. The time-activity curves of the SUV ratio (SUVR) of striatum over cerebellum were used as measure for specific uptake. Metabolism was investigated in CD-1 mice via radio-HPLC analysis of extracted plasma and brain samples. Single-dose acute toxicity of FLUDA was assessed in male and female Wistar rats.
A high A2aR binding affinity and high A1R selectivity were recorded for FLUDA (KiA2aR= 0.60 nM and KiA1R= XX nM). The two-step one-pot automated radiosynthesis of [18F]FLUDA was successfully established (radiochemical yield: 9±1%; radiochemical purity: ≥98%; molar activity= 69 333 GBq/µmol). In vitro autoradiography with [18F]FLUDA revealed a specific accumulation in the striatum, which is characterized by the binding parameters KD = 4.3 ± 0.7 nM and Bmax = 556 ± 143 fmol/mg wet weight (Fig.1A). In vivo evaluation in mice revealed that only the parent radiotracer was found in plasma and brain samples at 15 min p.i.. PET scans (n=3) showed a selective binding of [18F]FLUDA in striatum (SUVR15 30 min p.i.>8), which was significantly reduced by pre-treatment with 2.5 mg/kg i.p. tozadenant (30%, n=3, p<0.05, Fig.1B/C). The single dose toxicity study of FLUDA did not reveal any adverse effects for ~ 1000-fold of expected human dose.
The fully automated radiosynthesis of [18F]FLUDA allows its translation to clinical radiopharmacy. [18F]FLUDA exhibited a A2AR-specific accumulation in the striatum in vitro and in vivo. No safety concerns are expected upon administration of [18F]FLUDA according to toxicity and dosimetry studies. Altogether, these results encourage the performance of clinical trials to validate the potential of [18F]FLUDA for imaging of neuronal, cardiovascular and cancer-related diseases.
The authors thank the European Regional Development Fund and Sächsische Aufbaubank (SAB) for financial support (project no. 100226753).
 Kranz, M. et al. (2020) this volume.
Keywords: adenosine A2A receptor; [18F]FLUDA; PET; clinical translation
Contribution to proceedings
Society of Nuclear Medicine and Molecular Imaging Meeting (SNMMI 2020), 13.-16.06.2020, New Orleans, USA
The Journal of Nuclear Medicine, USA: Society of Nuclear Medicine and Molecular Imaging, S267
Process Metallurgy in Circular Economy System Design: The Copper and Base Metal Value Chain
Evaluating the economic viability as well as the sustainability of the Circular Economy (CE) system requires a deep understanding of the distribution of all elements, compounds, alloys, materials etc. in flows. In this paper, the circularity of the copper value chain, including primary and secondary processing, is rigorously evaluated. The studied system comprises the metallic copper production from primary sources (from mineral to metal), copper-containing commodity production (copper is mixed with other metals) and copper recycling through secondary smelting to close the loop. This is linked to photovoltaic (PV) panels and battery storage. A simulation model of this system is created using HSC Sim, considering more than 30 elements (and its various compounds), 180 unit operations and 800 flows. From the mass and energy balances obtained through the simulation, an exergy analysis is conducted to evaluate the resource consumption from a second law (entropy) perspective. Additionally, these results are complemented through a Life Cycle Assessment (LCA), the recovery of technology elements and by-products is discussed, while quantifying the losses through the value chain. Through the digitalization of the complete system, a better CAPEX and OPEX understanding of the metal recovery and losses can be obtained, as well as the associated resource consumption and environmental impacts. New flowsheets and technologies can be evaluated. Several scenarios show how the resource consumption and the environmental impacts are affected by the recovery of different materials to produce different products.
Keywords: Copper Value Chain; Exergy; Life Cycle Assessment; Process Simulation; Sustainability Evaluation
10th Copper International Conference, COPPER 2019 / Conference of Metallurgists, COM 2019, 18.-21.08.2019, Vancouver, Canada
Maxwell solver in PIC simulations
Keywords: pseudo-spectral time domain; particle-in-cell; finite difference
Invited lecture (Conferences)
CASUS Miniworkshop on Numerics, 13.-14.11.2019, Dresden, Deutschland
Modeling and understanding the dynamics of relativistic plasmas with particle-in-cell simulations
Keywords: particle-in-cell; plasma; laser particle acceleration
CASUS Opening Symposium, 26.-28.08.2019, Görlitz, Deutschland
Industrial By-Products as Non-Conventional Supplementary Cementitious Material
The extensive efforts on reducing the carbon footprint of cement production have motivated the investigations on the use of supplementary cementitious materials (SCM) as additive and/or substitute in cement blends. However, previous studies were focused on limited types of SCM including natural pozzolans, ground granulated blast furnace slag (GGBFS) and fly ash – which could readily exhibit reactivity in cementitious systems. In this article, a review on the advances in the valorisation of novel industrial by-products (non-ferrous slag, municipal incinerator bottom ash, and jarosite waste) are presented to provide solution in reducing the volume of industrial landfills while creating greener materials for building applications. The second part of this paper demonstrates a case study applying exergy to compare the footprint of the flowsheets derived from the valorisation of industrial by-products as SCM.
Keywords: green cements; slag; supplementary cementitious materials; bottom ash; jarosite; exergy; life cycle assessment
iiSBE Forum of Young Researchers in Sustainable Building, 01.07.2019, Prague, Czech Republic
Accelerator mass spectrometry: Detection of "One in a Quadrillion"
Für die Veranstaltung ist kein Abstract erforderlich.
Mass Spectrometry Christmas updates seminar, 17.12.2019, Dresden, Deutschland
HIFIS Software website: software.hifis.net
HIFIS Software Services' mission is to empower scientists of any domain to implement and to perpetuate modern scientific software development principles in order to make research software engineering more sustainable. The website of the platform is built using the static site generator Jekyll and available via https://software.hifis.net.
Keywords: Open Source; Software Engineering; Software; Development
Software in external data repository
Publication year 2019
System requirements: Firefox, Chrome, Safari, Edge
License: Code: GPLv3 Content: CC-BY-4.0 (Link to license text)
Hosted on HZDR GitLab: Link to location
Observation of sub-femtosecond structures in laser wakefield accelerated electron bunches
Laser wakefield accelerators (LWFA) feature unique electron bunch characteristics, namely micrometer beam size with duration ranging from a few fs to tens of fs. Precise knowledge of the longitudinal profile of such ultra-short electron bunches is essential for the design of future table-top x-ray light-sources.
Spectral measurements of broadband transition radiation from LWFA electron bunches passing through a metal foil are especially promising for non-destructively analyzing ultrashort longitudinal bunch characteristics with single-shot capability.
Our broadband, single-shot spectrometer combines the TR spectrum in UV/VIS (200-1000nm), NIR (0.9-1.7μm) and mid-IR (1.6-12μm). A complete characterization and calibration of the spectrometer have been done with regard to wavelengths, relative spectral sensitivities, and absolute photometric sensitivity. Our spectrometer is able to characterize electron bunches with charges as low as 1 pC and resolve time-scales from 0.4 to 40 fs. In addition, complementary data on the transverse bunch profile is provided by simultaneously imaging the CTR in the far- and near-field.
We present recent experimental results of different LWFA injection mechanisms, such as self-truncated ionization-injection and self-injection. By analyzing the transition radiation spectra and reconstructing electron bunch profiles including error analysis, we determine electron bunch profiles and peak currents of the respective injection regimes. In addition to bunch durations and peak currents, we discuss sub-fs beam micro-structures and systematic experimental scans of the nitrogen doping concentration for ionization-induced injection.
4th European Advanced Accelerator Concepts Workshop, 15.-21.09.2019, Elba, Italien
Characterization of the rotenone mouse model of Parkinson’s disease (PD) at early and late disease stage using radioligands for the α4β2 nicotinic acetylcholine receptor ((-)-[18F]Flubatine) and the adenosine A2A receptor ([18F]FESCH and [18F]FLUDA)
Toussaint, M.; Kranz, M.; Gündel, D.; Lai, T. H.; Schröder, S.; Dukic-Stefanovic, S.; Deuther-Conrad, W.; Teodoro, R.; Shang, Q.; Patt, M.; Reichmann, H.; Funk, R.; Sabri, O.; Pan-Montojo, F.; Brust, P.
Systemic administration of rotenone is able to reproduce the main pathological and behavioral hallmarks of Parkinson’s Disease (PD) in mice. Therefore, those mice are potentially useful for the development of therapies targeting the nicotinic acetylcholine receptor (α4β2nAChR) or the adenosine A2A receptor (A2AR).
Thus, we evaluated the ability of the rotenone model to resemble the decreased availability of α4β2nAChR and the increased availability of A2AR found in the brain of PD patients [1,2,3]. PET/MR imaging was performed to quantify these changes at early and later stages of the disease.
Two groups of 12-14-months-old male C57BL/6JRj mice (27-36 g) treated for 2 months (n=6) or 4 months (n=7) with rotenone, 5 days/week, 5 mg/kg p.o., and their corresponding control groups (n=7 and n=5, respectively) were investigated. (-)-[18F]Flubatine (6.4±1.9 MBq; Am: 1185±713GBq/μmol) for α4β2nAChR investigation and [18F]FESCH (5.0±1.8 MBq; Am: 116±19 GBq/μmol, EOS)  or [18F]FLUDA (5.7±1.2 MBq; Am: 96±10 GBq/μmol, EOS) for A2AR investigation were injected intravenously followed by 60 min dynamic PET scans. The cerebellum was used as a reference tissue. The time-activity curves (TACs) of the SUV ratio (SUVR) of thalamus or striatum over cerebellum were used as measure for specific uptake.
Specific uptake of (-)-[18F]Flubatine was observed in the thalamus of control and rotenone mice (SUVR60min p.i. ~3.5, all groups included). However, for none of the two treatment groups changes in α4β2nAChR availability compared to the control group were detected (figure 1).
Specific uptake of [18F]FESCH and [18F]FLUDA was observed in the striatum of control and rotenone mice (SUVR10-20 min p.i. ~4.8, all groups included) (figure 2).
PET scans revealed no significant differences in A2AR availability between control group and 2 months rotenone treatment group. However, the SUVR of the 4 months rotenone treatment group were higher compared to the control group (SUVR20-40 min p.i. 3.4 vs. 2.9, respectively), although statistically not significant due to the rather small and highly variable data set.
Altogether, the trend of these results indicates no accordance with clinical findings although a slightly increased availability of A2AR during the course of the disease can be mentioned.
Taking into account the high variability of the dataset, the investigation by PET/MR of the rotenone mouse model after 2 mo. and 4 mo. treatment shows no concordance with the clinical findings regarding α4β2nAChR and A2AR availabilities.
We assume that the rotenone mouse model might not be suitable to assess PD-related changes in the availability of the two targets and thus perhaps not suitable for the investigation of the related targeting-drug.
The European Regional Development Fund and Sächsische Aufbaubank are acknowledged for financial support (Project No. 100226753).
 Vuorimaa et al. Contrast Media Mol Imaging 2017; 6975841.  Meyer et al., Arch Gen Psych 2009, 66 : 866-877.  Cannon et al., Neurobiol Dis 2009 ; 34 : 279-90.  Khanapur et al., J Nucl Med 2017; 58: 466–472.
Keywords: Adenosine 2A receptor; α4β2 nicotinic acetylcholine receptor; rotenone mouse model of Parkinson's disease; positon emission tomography
15th European Molecular Imaging Meeting, 24.-27.03.2020, Thessaloniki, Greece
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